Authors - Department of Veterans' Affairs · Web viewUS forces withdrew from Iraq by December...

Systematic reviews of psychological disorders, multisymptom illness and chronic fatigue syndrome in veterans deployed to the Gulf War, Afghanistan or Iraq War

Technical Report 2015

Authors

Monash University

Dr Helen Kelsall

Professor Malcolm Sim

Professor Andrew Forbes

University of Melbourne

Professor Mark Creamer

Publications

Kelsall HL, Wijesinghe MSD, Creamer MC, McKenzie DP, Forbes AB, Page MJ, Sim MR. Alcohol

use and substance use disorders in Gulf War veterans compared to non-deployed military

personnel. Epidemiologic Reviews 2015; 37:38-54 38-54 doi:10.1093/epirev/mxu014

Blore JD, Sim MR, Forbes AB, Creamer MC, Kelsall HL. Depression in Gulf War veterans. A

systematic review and meta-analysis. Psychological Medicine 2015; 45(8):1565-1580

doi:10.1017/S0033291714001913

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AcknowledgementsThis research was supported by Applied Research Program Grant ARP1122 from the Australian

Department of Veterans’ Affairs (DVA).

We would like to acknowledge the contribution of several researchers and other individuals who

contributed to aspects of the project:

Ms Lorena Romero, Senior Librarian at the Alfred Health Ian Potter Library, for her advice in

developing and refining the search strategy for the multiple databases.

Dr Jed Blore for undertaking the initial search under the search strategy and his major

contribution to the paper on depression in Gulf War veterans.

Dr Supun Wijesinghe for his contribution to the systematic review and meta-analysis of alcohol

use and substance use disorders in Gulf War veterans.

Ms Stella Gwini, who contributed to the review and meta-analysis of multisymptom illness.

Dr Matthew Page for his assistance in completing the statistical analyses.

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Table of contentsAuthors...............................................................................................................................................2

Publications.....................................................................................................................2

Acknowledgements............................................................................................................................3

Table of contents................................................................................................................................4

List of Tables......................................................................................................................................6

List of Figures.....................................................................................................................................8

Abbreviations...................................................................................................................................11

1 Introduction...............................................................................................................................13

2 Aims..........................................................................................................................................15

3 Method......................................................................................................................................16

3.1 Health outcomes considered and definitions...................................................................16

3.2 Search strategy and selection criteria..............................................................................17

3.3 Study selection and data extraction.................................................................................19

3.4 Risk of bias assessment..................................................................................................21

3.5 Analytical strategy............................................................................................................21

4 Psychological disorders in Gulf War, Afghanistan and Iraq War veterans compared to non-

deployed military personnel......................................................................................................24

4.1 Literature search results..................................................................................................24

4.2 Depression in Gulf War veterans compared to non-deployed military personnel............26

4.2.1 Results.............................................................................................................26

4.2.2 Key findings.....................................................................................................28

4.3 Depression in Afghanistan/Iraq War veterans compared to non-deployed military

personnel.........................................................................................................................34

4.3.1 Results.............................................................................................................34

4.3.2 Key findings.....................................................................................................45

4.4 PTSD in Gulf War veterans compared to non-deployed military personnel....................46

4

4.4.1 Results.............................................................................................................46

4.4.2 Key findings.....................................................................................................62

4.5 PTSD in Afghanistan/Iraq War veterans compared to non-deployed military personnel.63

4.5.1 Results.............................................................................................................63

4.5.2 Key findings.....................................................................................................78

4.6 Alcohol use and substance use disorders in Gulf War and Afghanistan/Iraq War veterans

compared to non-deployed military personnel.................................................................79

4.6.1 Results.............................................................................................................79

4.6.2 Key findings.....................................................................................................96

4.7 Generalised anxiety disorder in Gulf War and Afghanistan/Iraq War veterans compared

to non-deployed military personnel..................................................................................97

4.7.1 Results.............................................................................................................97

4.7.2 Key findings...................................................................................................107

5 Multisymptom illness in Gulf War, Afghanistan and Iraq War veterans compared to non-

deployed military personnel....................................................................................................108

5.1 Literature search results................................................................................................108

5.2 Multisymptom illness in Gulf War veterans compared to non-deployed military personnel

109

5.2.1 Results...........................................................................................................109

5.2.2 Key findings...................................................................................................116

6 Chronic fatigue syndrome in Gulf War, Afghanistan and Iraq War veterans compared to non-

deployed military personnel....................................................................................................117

6.1 Literature search results................................................................................................117

6.2 CFS in Gulf War veterans compared to non-deployed military personnel.....................118

6.2.1 Results...........................................................................................................118

6.2.2 Key findings...................................................................................................119

7 Discussion...............................................................................................................................124

8 Implications of findings............................................................................................................127

9 Implications for future research...............................................................................................129

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10 Conclusion...............................................................................................................................130

11 References..............................................................................................................................132

6

List of TablesTable 1 Characteristics of eligible studies comparing prevalence of depression in Gulf War

veterans and non-deployed military personnel................................................................................29

Table 2 Sensitivity analyses excluding each study one by one for studies of depression in

Afghanistan/Iraq War veterans compared to non-deployed military personnel...............................38

Table 3 Characteristics of eligible studies comparing prevalence of depression in Afghanistan/Iraq

War veterans and non-deployed military personnel.........................................................................40

Table 4 Sensitivity analyses excluding each study one by one for studies of PTSD in Gulf War

veterans compared to non-deployed military personnel..................................................................51

Table 5 Characteristics of eligible studies comparing prevalence of PTSD in Gulf War veterans and

non-deployed military personnel......................................................................................................53

Table 6 Sensitivity analyses excluding each study one by one for studies of PTSD in

Afghanistan/Iraq War veterans compared to non-deployed military personnel...............................68

Table 7 Characteristics of eligible studies comparing prevalence of PTSD in Afghanistan/Iraq War


Table 8 Characteristics of eligible studies comparing prevalence of alcohol/substance use

disorders in Gulf War veterans and non-deployed military personnel.............................................85

Table 9 Characteristics of eligible studies comparing prevalence of alcohol/substance use

disorders in Afghanistan/Iraq War veterans and non-deployed military personnel..........................90

Table 10 Characteristics of eligible studies comparing prevalence of generalised anxiety disorder

(GAD) in Gulf War veterans and non-deployed military personnel................................................103

Table 11 Characteristics of eligible studies comparing prevalence of generalised anxiety disorder

(GAD) in Afghanistan/Iraq War veterans and non-deployed military personnel............................105

Table 12 Sensitivity analyses excluding each study one by one for studies of multisymptom illness

in Gulf War veterans compared to non-deployed military personnel.............................................111

Table 13 Characteristics of eligible studies comparing prevalence of multisymptom illness in Gulf

War veterans and non-deployed military personnel.......................................................................112

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Table 14 Sensitivity analyses excluding each study one by one for studies of CFS in Gulf War

veterans compared to non-deployed military personnel................................................................119

Table 15 Characteristics of eligible studies comparing prevalence of chronic fatigue syndrome

(CFS) and CFS-like illness in Gulf War veterans and non-deployed military personnel................120

Table 16 Main meta-analysis summary odds ratios for psychological disorders, multisymptom

illness and chronic fatigue syndrome (CFS) in Gulf War, Afghanistan/Iraq War veterans compared

with non-deployed personnel.........................................................................................................124

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List of FiguresFigure 1: PRISMA flowchart of the systematic review of psychological disorders in Gulf War

veterans, Afghanistan/Iraq War veterans, 1990-2014......................................................................25

Figure 2 Random effects meta-analysis of depression in Gulf War veterans compared to non-

deployed military personnel.............................................................................................................27

Figure 3 Random effects meta-analysis of dysthymia or chronic dysphoria in Gulf War veterans

compared to non-deployed military personnel.................................................................................28

Figure 4 Random effects meta-analysis of depression in Afghanistan/Iraq War veterans compared

to non-deployed military...................................................................................................................34

Figure 5 Random-effects meta-analysis of depression in Afghanistan/Iraq War veterans compared

to non-deployed military personnel, subgrouped by type of outcome measure...............................35


to non-deployed military personnel, subgrouped by type of service................................................36


to non-deployed military personnel, subgrouped by risk of bias......................................................37


to non-deployed military personnel, subgrouped by adjustment of odds ratios...............................38

Figure 9 Funnel plot for the random-effects meta-analysis of depression in Afghanistan/Iraq War

veterans compared to non-deployed military personnel..................................................................39

Figure 10 Random-effects meta-analysis of PTSD in Gulf War veterans and non-deployed military

personnel.........................................................................................................................................46


personnel, subgrouped by type of outcome measure......................................................................47


personnel, subgrouped by type of service.......................................................................................48


personnel, subgrouped by risk of bias.............................................................................................49

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personnel, subgrouped by adjustment of odds ratios......................................................................50

Figure 15 Funnel plot for the random-effects meta-analysis of PTSD in Gulf War veterans and non-


Figure 16 Random-effects meta-analysis of PTSD in Afghanistan/Iraq War veterans and non-



deployed military personnel, subgrouped by type of outcome measure..........................................64


deployed military personnel, subgrouped by type of service...........................................................65


deployed military personnel, subgrouped by risk of bias.................................................................66


deployed military personnel, subgrouped by adjustment of odds ratios..........................................67

Figure 21 Funnel plot for the random-effects meta-analysis of PTSD in Afghanistan/Iraq War


Figure 22 Random-effects meta-analysis illustrating log-transformed odds ratios of alcohol use

disorders in Gulf War veterans and non-deployed military personnel.............................................80

Figure 23 Random-effects meta-analysis illustrating log-transformed odds ratios of any substance

use disorders in Gulf War veterans and non-deployed military personnel.......................................82

Figure 24 Random-effects meta-analysis illustrating log-transformed odds ratios of alcohol use


Figure 25 Random-effects meta-analysis illustrating log-transformed odds ratios of substance use


Figure 26 Random-effects meta-analysis illustrating log-transformed odds ratios of generalised

anxiety disorder in Gulf War veterans and non-deployed military personnel...................................98

Figure 27 Random-effects meta-analysis of generalised anxiety disorder in Gulf War veterans and

non-deployed military personnel, subgrouped by case definition....................................................99

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Figure 28 Random-effects meta-analysis of generalised anxiety disorder in Gulf War veterans and

non-deployed military personnel, subgrouped by risk of bias........................................................100

Figure 29 Random-effects meta-analysis illustrating log-transformed odds ratios of generalised

anxiety disorder in Afghanistan/Iraq War veterans and non-deployed military personnel.............101

Figure 30 Random-effects meta-analysis of GAD in Afghanistan/Iraq War veterans compared to

non-deployed military personnel, sensitivity analysis excluding Bray (2006)................................102

Figure 31 Flowchart of the systematic review of multisymptom illness (MSI) Gulf War veterans,

Afghanistan/Iraq War veterans, 1990-2014...................................................................................108

Figure 32 Random-effects meta-analysis of multisymptom illness in Gulf War veterans and non-

deployed military personnel...........................................................................................................110

Figure 33 Funnel plot for the random-effects meta-analysis of multisymptom illness Gulf War

veterans and non-deployed military personnel..............................................................................111

Figure 34 PRISMA flow diagram for chronic fatigue syndrome (CFS) in Gulf War, Afghanistan, Iraq

War veterans..................................................................................................................................117

Figure 35 Random-effects meta-analysis illustrating log-transformed odds ratios of chronic fatigue

syndrome in Gulf War veterans and non-deployed military personnel..........................................118

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AbbreviationsAUDIT World Health Organization Alcohol use disorder identification testARP (Department of Veterans’ Affairs) Applied Research ProgramAUD Alcohol use disordersBDI Beck Depression IndexBMI Body Mass IndexCAGE CAGE QuestionnaireCAPS Clinician Administered PTSD ScaleCES-D Center for Epidemiologic Studies Depression ScaleCFS Chronic fatigue syndromeCI Confidence intervalCIDI World Health Organization Composite International Diagnostic InterviewCIDI–SF World Health Organization Composite International Diagnostic Interview

Short FormCDC Centers for Disease Control and Prevention, Atlanta, Georgia(combined) any SUD (combined) any substance use disorder refers to alcohol use disorders

and other substance use disorders combinedDoD (US) Department of DefenseDSM Diagnostic and Statistical Manual of Mental Disorders, American

Psychiatric AssociationFE MA Fixed effects meta-analysis (as appears in the funnel plot figures)GAD Generalised anxiety disorderGW Gulf WarGWV/s Gulf War veteran/sICD-9 International Classification of Diseases, 9th RevisionIOM Institute of MedicineMDD Major depressive disorderMeSH Medical Subject HeadingsMEAO Middle East Area of OperationsM-PTSD Mississippi scale for combat-related PTSDMSI Multisymptom illnessNCO Non-commissioned officerNG National GuardNG/Res National Guard/ReserveOEF Operation Enduring Freedom (Afghanistan)OIF Operation Iraqi FreedomOR Odds ratioPCL PTSD Checklist

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PCL-C PTSD Checklist – Civilian versionPCL-M PTSD Checklist – Military versionPDHA Post-Deployment Health AssessmentPHQ Patient Health QuestionnairePRIME-MD PHQ Primary Care Evaluation of Mental Disorders Patient Health QuestionnairePTSD Posttraumatic stress disorderR Regular militaryRR Relative RiskSCID Structured Clinical Interview for DSM DisordersSD Standard deviationSUD Substance use disorders (for brevity in this report is used to refer to

substance use disorders other than alcohol use disorders, e.g. opioids, sedatives, anxiolytics, cocaine, cannabis)

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1 IntroductionIn the 1990-1991 Gulf War, a large multinational force was deployed to the Gulf area in response

to the invasion of Kuwait by Iraq on 2 August 1990. In October 2001, in response to the

September 11 attacks on the US, the United States of America (US) supported by the United

Kingdom (UK), Australia, Canada, France and Germany and other nations began an invasion of

Afghanistan (Operation Enduring Freedom). In March 2003, the Iraq War began (Operation Iraqi

Freedom) when a combined force from the US, UK, Australia and Poland invaded Iraq. US forces

withdrew from Iraq by December 2011.

The forces deployed by different countries differed. For example, in contrast to US service

members and UK personnel deployed during the 1990-1991 Gulf War who were predominantly

army land based forces, Australian personnel were primarily involved in sea and air surveillance

(around 85% of deployed personnel were in the Royal Australian Navy) (1). In the Afghanistan and

Iraq War operations, the Australian deployment involved the services of Air Force, Navy, Army,

and Special Operations Task Group (2). The Army comprised the majority of deployed UK (3) and

US active-duty (4) personnel.

Psychological and physical health is important to all military personnel, deployed personnel,

veterans and their families. Studies of the relationship between deployment to the Gulf War and to

the Afghanistan/Iraq War and health outcomes suggest that veterans of these wars are at

increased risk of psychological illnesses compared to personnel not deployed to these conflicts (5-

10). Posttraumatic stress disorder (PTSD) has tended to receive greater attention and publicity

than other psychological disorders such as affective disorders, anxiety disorders such as

generalised anxiety disorder (GAD), or substance use disorders (11), yet alcohol and other

substance use disorders have also long been associated with combat experience in other theatres

of war (12-14).

There have been several previous reviews of health outcomes, but these have mainly been in Gulf

War veterans, and since these earlier reviews further studies have been conducted and so they do

not include more recently published findings, or were narrative in style rather than systematic.

Stimpson et al. (11) conducted a systematic review of psychiatric disorders in veterans of the

1990-1991 Gulf War which was published in 2003. The Stimpson review found that, despite

heterogeneity between the studies examined, the prevalence of PTSD and common mental

disorder (depression or anxiety diagnosed using a standardised assessment or self-reported

depression symptoms on a checklist) was increased in Gulf War veterans compared with a non-

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http://en.wikipedia.org/wiki/Iraq

http://en.wikipedia.org/wiki/Poland

Gulf comparison group. The search strategy for Stimpson et al.’s (11) review ended in May 2001,

with the last reviewed study being published in 2001.

Thomas et al. (2006) (15) conducted a systematic review of symptom-based conditions (termed

multi-symptom conditions in the review) in Gulf War veterans, including the Centers for Disease

Control and Prevention (CDC)-defined multisymptom illness for papers published between 1990

and 2004, and found that Gulf War deployment was strongly associated with chronic fatigue

syndrome (CFS) and Gulf War veterans were more likely to report multiple chemical sensitivity or

chronic multisymptom illness, as defined by CDC. The review showed that there was considerable

variation in the methodological quality of the studies identified, and noted that the later and larger

studies were of a higher methodological quality (15). The search strategy for the Thomas et al (15)

review concluded in May 2004 and the last reviewed study was published in 2004.

There has been further research conducted among Gulf War veterans since these review papers

were published and this justified further reviews. Numerous studies have been published on the

psychological health of Gulf War veterans, including that of Australian veterans (1, 16), and of

reports of increased rates of anxiety (17) and depression (18) in US Gulf War veterans, and

several on multisymptom illness and CFS, including those of Australian and US Gulf War veterans

(16, 19-21). An Institute of Medicine (IOM) Gulf War and Health report published in 2010 (22)

provided a comprehensive summary report of primary and secondary studies, according to its

criteria, published since the IOM 2006 report (23) on Gulf War veteran health (11). The IOM report

was a narrative review and did not include any meta-analyses.

Furthermore, there have been an increasing number of published studies reporting the

psychological health of the Afghanistan and Iraq War veteran cohorts, which are increasingly

relevant and have also reported adverse psychological health outcomes.

One review, conducted by Kok et al. (24) and published in 2012, examined PTSD in military

personnel deployed to the Afghanistan and Iraq Wars. However, the authors did not restrict

studies for inclusion based on the presence of an appropriate comparison group and therefore

could not determine the odds of deployed personnel developing PTSD compared to non-deployed

personnel. Another review, conducted by Sundin et al. (25) and published in 2010, investigated

PTSD in Iraq deployed personnel only. Like the study by Kok et al. (24), this study did not report

the odds of developing PTSD in those deploying to Iraq compared to non-deployed personnel. A

third review, conducted by Gadermann et al. (26) and published in 2012, investigated major

depression in US personnel only, and as in the previous reviews, no restrictions were placed on

studies not including a comparison group. Results were also not reported by deployment.

15

It has been widely acknowledged that exposure to combat and other wartime experiences can

have both short-term and long-term psychological and physical effects. However, reported

psychological consequences have been quite varied. Therefore, undertaking a systematic review

assists in drawing conclusions about consistency of the results of studies in relation to health

outcomes in Gulf War veterans, Afghanistan and Iraq War veterans compared to personnel who

were not deployed to the corresponding warzone or who were deployed elsewhere. Conducting

meta-analyses and presenting the output produces visual and comparable summary effect

estimates of the health outcomes under consideration in Gulf War veterans, Afghanistan and Iraq

War veterans compared with non-deployed military personnel, and quantifies these in overall

summary measures.

A pattern of increased reporting of symptoms across several body systems has been reported in

several Gulf War veteran health epidemiological studies. In 1998 Fukuda et al. (27) developed a

case definition for multisymptom illness in Gulf War veterans, also known as the CDC definition.

This has been an accepted definition adopted by many research groups to define multisymptom

illness in further Gulf War veteran health epidemiological studies. Other definitions of

multisymptom illness have been suggested by Haley et al. (1997) (28), Steele et al. (2000) (29),

Bourdette (2001) (30), and Kang et al. (2009) (31), and these either exert more stringent rules on

the classification of the illness or use variations or slightly different methods to elucidate the

patterns of multisymptom reporting.

The body of research on psychological health and, to a lesser extent on physical health, of

veterans of deployments to the 1991 Gulf War, Afghanistan and Iraq War has grown considerably

in the past few years. Publication of further research since review papers were published has

justified further reviews in relation to psychological health outcomes. Furthermore, to our

knowledge a systematic review of any literature reporting symptom based conditions of

multisymptom illness and CFS in veterans of deployments to Afghanistan and the Iraq War has not

been undertaken. A systematic review that considers all the research done on the topic in these

veteran cohorts and presents summary estimates can provide a useful summary for practitioners

and policy makers.

The purpose of this project was to conduct systematic reviews and meta-analyses of studies that

have compared psychological disorders, multisymptom illness and CFS in veterans of deployments

to the 1991 Gulf War, Afghanistan or the Iraq War, compared to military personnel who were not

deployed to these conflicts.

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2 AimsThe overall aim of this project was to conduct systematic reviews and meta-analyses of the

international literature to compare psychological disorders (depression, PTSD, GAD, alcohol use

disorders, other substance use disorders (e.g. opioids, sedatives, anxiolytics, cocaine, cannabis)

(herein termed substance use disorders for brevity), multisymptom illness and CFS in veterans of

the Gulf War, Afghanistan and Iraq War compared with non-deployed comparison groups of the

corresponding conflicts. A further aim in the meta-analyses was to assess sources of variability, by

subgroup analyses relevant to the particular meta-analysis being undertaken, to explore the factors

most likely to result in study heterogeneity.

3 MethodThe searches, study selection and data extraction were conducted separately for psychological

disorders, multisymptom illness and CFS; but as the methods were similar for the three broad

outcome categories in Gulf War veterans, Afghanistan and Iraq War veterans, this section

describes the methods overall. The results are then presented separately for each of these three

broad outcomes.

3.1 Health outcomes considered and definitions

The health outcomes considered were:

Psychological disorders of depression (major depression and dysthymia), PTSD, GAD,

alcohol use disorders, substance use disorders and (combined) any substance use

disorder (i.e. alcohol and/or substance use disorders),

Multisymptom illness, and

CFS.

The psychological disorders reviewed are the more commonly reported psychological conditions,

and for which assessment measures were considered likely to be more homogeneous between

studies of veterans from different countries. Although GAD was not proposed as a psychological

disorder for inclusion in the Detailed Project Plan, it is the most commonly diagnosed anxiety

disorder world-wide (32) but has received relatively little attention in military or veteran populations.

There were sufficient papers to review and to conduct a meta-analysis, and thus this outcome was

included.

17

During the conduct of this project and these systematic reviews and meta-analyses, the prevailing

classification system for psychological disorders was DSM-IV (American Psychiatric Association

Diagnostic and Statistical Manual of Mental Disorders, 4th edition) (33), and both posttraumatic

stress disorder and generalised anxiety disorder were classified under Anxiety Disorders. In DSM-

V, published in 2013, posttraumatic stress disorder was classified under Trauma- and Stressor-

Related Disorders (34). Materially this does not make any difference to the findings of these

systematic reviews.

Alcohol use disorders, and substance use disorders (i.e. relating to drugs of abuse other than

alcohol such as amphetamine or similarly acting sympathomimetics, cannabis, cocaine,

hallucinogens and opioids; phencyclidine (PCP), or similarly acting arylcylcohexylamines; and

sedatives, hypnotics, or anxiolytics, as defined in the corresponding studies; herein in this report

referred to as substance use disorders) were reported separately in the systematic reviews and

meta-analyses where possible. Some studies reported an outcome that combined alcohol use

disorders and substance use disorders; and were referred to as (combined) any substance use

disorder to differentiate the outcome from substance use disorders. In a meta-analysis of any

substance use disorder, we also included studies that had reported alcohol use and substance use

disorders outcomes.

The definition used for inclusion of studies of multisymptom illness was based on an internationally

accepted definition, specifically the CDC definition (20, 27) developed by Fukuda et al. (27) and its

variants. The CDC definition identifies multisymptom illness as present if the person has one or

more chronic symptoms (for at least six months) from at least two of three categories: fatigue,

mood-cognition (symptoms of feeling depressed, difficulty remembering or concentrating, feeling

moody, feeling anxious, trouble finding the right words or difficulty sleeping) and musculoskeletal

(symptoms of joint pain, joint stiffness or muscle pain), where the latter were the two categories

identified in their factor analysis of symptoms reported in their study of US Gulf War veterans. For

this systematic review, we used the CDC definition of multisymptom illness because it represented

an internationally accepted definition of multisystem symptom reporting and was commonly

available during the period of the review.

The definition used for inclusion of studies of CFS was based on an internationally accepted

definition, specifically the 1994 international definition (19, 35) for defining CFS and other fatiguing

illnesses.

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3.2 Search strategy and selection criteria

The scientific literature was searched for published and unpublished citations from 1 January 1990

to 24 January 2014 using multiple electronic databases MEDLINE, MEDLINE In-Process,

PsycINFO, Embase, Published International Literature on Traumatic Stress (PILOTS) and

Cochrane Reviews. In the multisymptom illness search, the System for Information on Grey

Literature in Europe (SIGLE) was also included. Additional sources searched for non-peer review

literature included the US, UK and Australian departments of veterans’ affairs and departments of

defence websites.

Studies which matched the following inclusion criteria were included:

[1] The study population consisted of military personnel deployed to the Gulf War (1990-1991),

Afghanistan (2001- ) or Iraq War (2003-2011) encompassing Navy, Army, Air Force, Marines,

Coast Guard, medical personnel, and Reservists/National Guard;

[2] Studies were published in English;

[3] The outcome of interest was depression (major depression and dysthymia), PTSD, GAD,

alcohol use disorders, substance use disorders, (combined) any substance use disorder,

multisymptom illness defined using a definition similar to the CDC definition or its variants; or

CFS;

[4] The study included a military comparison group that differed in its level of deployment

exposure to the corresponding conflict (non-deployed personnel were defined as personnel

who did not serve in the primary area of conflict as per previous systematic reviews (36), and

other conflict/other deployed personnel were defined as personnel deployed outside the

primary area of conflict or to other conflicts, e.g. Germany, Bosnia); and

[5] For inclusion in the meta-analysis, the study needed to provide enough information to

generate an odds ratio (OR) by deployment.

Studies of the following type were excluded from the review:

[1] The conflict deployed sample was of non-military personnel;

[2] Studies that were published in a language other than English;

19

[3] The sample was based on clinical or injured or treatment/help-seeking population/s

(including studies based on data from Veterans Affairs (VA) treatment facilities);

[4] Studies with no eligible military comparison group (e.g. civilians were used as a comparison

group) or where it was not clear where the population being studied had been deployed; and

[5] In the multisymptom review, studies where the definition of multisymptom condition did not

accord with a multisystem condition in accordance with the CDC criteria, e.g. a total symptom

count was used.

We developed a list of free text and Medical Subject Headings (MeSH) terms based on the three

components in the research question. The components were “A1: Gulf War, Afghanistan War and

Iraq War”, “A2: Military personnel, military veterans, military medicine, and veterans’ health” and

“B: Psychological disorders”. The final search strategy was: (A1 or A2) AND (B). Key words were

customised to each individual database. A modified portion of the search string that was used for

Medline database in searching for psychological disorders is given below.

(exp Gulf War/ OR Persian Gulf War OR Gulf* OR Desert Storm OR Desert Shield OR exp Afghan

Campaign 2001-/ OR Afghan* OR Enduring Freedom* OR OEF OR exp Iraq War, 2003-/ OR I* OR

Iraqi Freedom* OR OIF OR TELIC OR New Dawn OR OND) OR (exp Military Personnel/ OR

Military Veterans OR military* OR service personnel OR soldier* OR active duty OR deployed*)

AND (alcohol* OR substance use OR substance abuse OR substance dependence OR drug

abuse OR drug use OR drug misuse OR drug dependence OR illicit drug* OR illicit substance* OR

substance misuse OR recreational drug* OR illegal substance* OR illegal drug* OR drug disorder*

OR (substance adj2 disorder)) OR (exp depression/ OR (depress* OR dysthymi* or melancholi*))

OR (exp generalized anxiety disorder/ OR (generalised anxiety disorder OR GAD*)).

Similarly, the multisymptom illness search terms were based on the free-text and MeSH of the

condition of interest (multisymptom or multi-symptom or multiple-symptom or multiple symptom or

CMI or Gulf War Illness* or unexplained illness* or CDC or Persian Gulf syndrome* or Gulf War

syndrome* or Persian Gulf Illness* or Gulf War Illness*) and the area of operation (as defined

above).

The CFS literature search terms were based on the free-text and MeSH of the condition of interest

(chronic fatigue or chronic-fatigue or CFS or CDC-fatigue or CDC fatigue or Chalder fatigue or

Chalder-fatigue or fatigue) and the area of operation (as defined above).

20

3.3 Study selection and data extraction

The search strategy and selection of studies was conducted according to PRISMA (Preferred

Reporting Items for Systematic Reviews and Meta-Analyses) recommendations (37). Titles and

abstracts (records) from each database were entered into the reference manager software,

EndNote version X4. Duplicates were removed. These records were screened to identify studies

for full-text review by the specified inclusion and exclusion criteria above. A member of the

research team reviewed all titles and abstracts, and HK conducted a blind review of approximately

ten per cent of titles and abstracts to refine and discuss any amendments to the reviewing strategy,

and all abstracts selected for full-text review and all eligible articles. Any discrepancies were

resolved through collaboration.

Quantitative and other relevant data for each individual study were extracted by standard data

extraction forms developed for the review (descriptive data, summary measures of effect size,

precision and assessment of risk of bias) and tabulated including first author, study design, date

and location, method of data collection, sample size including female percentage, psychological

health outcome measure and case definition used in the study, participation rates, assessment of

risk of bias, overall risk of bias assessment (see later) of each individual study, outcome of interest

as a prevalence in the Gulf War, Afghanistan, Iraq War veterans and comparison group,

unadjusted association estimates (odds ratio, OR) and adjusted (for potential confounding factors

such as age, service branch, rank) association estimates (OR) of the same.

We used the following pre-defined strategy for extracting data to be included in the meta-analysis.

Studies that were derivative studies of earlier studies and did not present new data were not

included in the review. If two papers reported an overlapping sample of participants, we prioritised

inclusion of results of the larger sample in the meta-analysis. Where more than one paper from the

same study population, or the same paper, reported the same or a similar outcome measure,

priority was given to the most valid and reliable psychological outcome case definition. The priority

order was as follows: 1) structured diagnostic interview or diagnosis made by a clinician (38); 2)

screening tool; (e.g., Patient Health Questionnaire (PHQ; Beck Depression Inventory (BDI),

Alcohol use disorder identification test (AUDIT); 3) self-reported physician diagnosis (39, 40).

Data were extracted by a member of the team and checked by HK independently and any

discrepancies were resolved through discussion. Where results were given for both non-deployed

and other-deployed comparison groups, results for the non-deployed comparison group were given

priority. Reported adjusted ORs were prioritised over unadjusted ORs and unadjusted ORs over

prevalences. Where studies did not provide an OR, these were calculated using the reported

prevalence, or numbers of deployed and non-deployed veterans with and without the psychological

disorder, and subsequently entered into the meta-analysis along with the adjusted ORs from other

21

studies. When data were not presented in the desired categories of deployed vs non-deployed,

results were recalculated using the reported prevalences and numbers (n’s).

By definition in this report, Non-deployed / non-GWV refers to a military comparison group who

were not deployed to the Gulf War during the period of operations, and Non-deployed / non-

Afghanistan/Iraq War veteran refers to a military comparison group who were not deployed to the

Afghanistan/Iraq War during the period of operations.

3.4 Risk of bias assessment

The PRISMA statement (37) notes that the reporting of assessment of risk of bias in included

studies is important in the conduct of systematic reviews. ‘Risk of bias’ refers to ‘systematic error

or deviation from the truth, in results or inferences’ (41).

Overall risk of bias of the studies included in this systematic review was assessed using an

instrument developed by Hoy et al. (42) which was used for the assessment of prevalence studies

in the Global Burden of Disease Study 2010 (43).

This instrument is reported to have a high overall inter-rater agreement of 91%, with a kappa

statistic (44) representing chance-corrected agreement of 0.82 (95% confidence interval (CI): 0.76,

0.86). This tool enables an overall risk of study bias based on assessment of the risk of bias of 10

individual items (items 1-4 and items 5-10 of this instrument are based on external and internal

validity of the included study, respectively). We included an additional item on availability of, and

adjustment for, possible confounding factors since it was expected there would be considerable

variation in the extent to which the individual studies attempted to adjust for confounding factors

(11). Individual items were assessed as high and low risk of bias, and used to assess overall risk

of bias. The authors of the tool had deliberately excluded a moderate risk of bias category as

testing indicated this was being used to avoid deciding between high and low risk of bias;

subsequently inter-rater agreement improved substantially (42).

3.5 Analytical strategy

In all meta-analyses (37) we prioritised inclusion of adjusted (for possible confounders such as

age, education, branch of service, and duty status, etc) OR over unadjusted OR and unadjusted

OR over simple prevalence figures. Where data were not presented in the desired categories of

deployed v non-deployed, results were recalculated using the reported prevalences and n’s. In

cases where the prevalence of CFS was zero in one group, the OR was calculated using RevMan

software, which adds 0.5 to all cells where zero cells cause problems with computation of effect

22

estimates or standard errors (45). All the measures of association were converted into OR and

corresponding 95% CI for studies that did not present them in the original manuscripts. As

heterogeneity of outcome was expected between studies, random effects meta-analyses (46, 47),

for the outcomes under consideration were conducted to aggregate the OR across the selected

studies and produce pooled odds ratios with 95% CI based on the standard normal distribution.

After study selection for multisymptom illness, it was identified that one study had reported results

separately for males and females and hence these results were aggregated using formulas

adapted from McNeil (48).

Statistical heterogeneity was reported using the I2 statistic which indicates variability in results

across studies that is due to heterogeneity rather than chance. I2 ranges between 0% to 100% with

higher values representing greater heterogeneity (49). Corresponding P-values indicate the

significance of the heterogeneity.

Sources of variability were assessed by subgroup analyses relevant to the particular meta-

analyses being undertaken, to explore the factors most likely to result in study heterogeneity.

These included the outcome measure used (diagnostic interview; screening tool; self-reported

physician diagnosis), type of multisymptom definition, adjusted vs unadjusted odds ratios, risk of

bias (low, high), theatre of deployment (Gulf War versus Afghanistan/Iraq War), and duty status

(regular versus reservist) in Gulf War and Afghanistan/Iraq War veterans. If results were originally

presented separately for personnel deployed to Afghanistan or Iraq, they are tabulated as such.

In the multisymptom illness review and meta-analysis, two studies were identified which had been

conducted by the same research group (21, 31) and possibly with an overlap of participants.

Hence we repeated the analyses using Bayesian random effects models with `delta splitting’ to

accommodate the overlap of participants, computed using the metahdep function in the R software

(50, 51). Since results differed negligibly from the conventional random effects analysis we report

only the conventional random effects results here.

To investigate whether there was a relationship between sources of variability and the magnitude

of the odds ratios, we undertook random effects meta-regression (52). Sensitivity analyses,

excluding studies one by one for the relevant health outcome under consideration, were conducted

for both Gulf War and Afghanistan/Iraq War veteran studies.

Publication bias was assessed by generated funnel plots (53) and by conducting the Egger test for

funnel plot asymmetry (49, 54, 55), using Stata version 11.0 or 12.0 software (StataCorp LP,

College Station, Texas) (56). A P-value of <0.05 was considered statistically significant for the

Egger test indicating funnel plot asymmetry.

23

A funnel plot is a graphical display of a measure of study precision plotted, most commonly on the

vertical axis, against effect estimate, on the horizontal axis, that can be used to investigate whether

there is a link between study size and effect estimate. One possible cause of an observed

association is reporting bias (57).

The term ‘funnel plot’ arises from the fact that precision of the effect estimate increases as the size

of the study increases, therefore effect estimates from small studies will scatter more widely at the

bottom of the graph and the spread will narrow among larger studies (41). In the absence of

publication bias, i.e. smaller studies without statistically significant effects were also published; the

plot should approximately resemble a symmetrical, inverted funnel. The more pronounced the

asymmetry, the more likely it is that the amount of bias could be greater (41).

Some problems with interpretation of funnel plots have been identified (41); for example that

publication bias need not lead to asymmetry in funnel plots (41), and that interpretation should not

be based on visual inspection alone (55), and spurious asymmetry as some effect estimates are

naturally correlated with their standard errors (41). Inferences on the presence of bias or

heterogeneity need to consider different causes of funnel plot asymmetry and be informed by

contextual factors, including publication bias as a plausible explanation for the asymmetry (55). In

the systematic reviews and meta-analyses in this report, publication bias was assessed by

generated funnel plots (53), by conducting the statistical Egger test for funnel plot asymmetry (49,

54, 55), and by considered interpretation.

A forest plot is a graphical representation of the individual results of each study included in a meta-

analysis together with the combined summary meta-analysis result (57). The individual study

results are shown as squares centred on each study’s point estimate, and the horizontal line

running through each square shows the 95% CI. The subgroup analyses estimates or the overall

summary estimate from the meta-analysis and their 95% CI are shown at the bottom of each

subgroup analysis or at the bottom of the figure, represented as diamonds. The centre of the

diamond represents the pooled point estimate, and its horizontal tips represent the CI. A forest plot

also allows readers to visually see the heterogeneity among the results of the studies (57).

All meta-analyses were performed using MetaXL 1.1 for analysis of depression in Gulf War

veterans or MetaXL version 1.4 (http://www.epigear.com) (58). Meta-regressions were conducted

using the metareg command in Stata (59).

24

4 Psychological disorders in Gulf War, Afghanistan and Iraq War veterans compared to non-deployed military personnel

4.1 Literature search results

Figure 1 shows that the search for psychological health outcomes under study yielded 23,533

records, with 14,771 records remaining after removal of duplicates. Following the removal of

duplicates, titles and abstracts were screened to identify studies for full- text review by the

specified inclusion and exclusion criteria. After abstract review, 253 full-text articles were identified

for further review and were reviewed separately in relation to Gulf War or Iraq/Afghanistan

psychological disorders’ eligibility. Of these, in relation to Gulf War eligibility, 228 were excluded

and, in relation to Iraq/Afghanistan eligibility, 224 were excluded. The reasons for exclusion are

identified in Figure 1. Forty-nine eligible articles were identified reporting psychological disorders,

25 in Gulf War veterans and 24 in Afghanistan/Iraq War veterans.

25

14,771 Records After Duplicates Removed

14,771 Records Screened 13,903 Titles Excluded

868 Abstracts Assessed For Eligibility 615 Abstracts Excluded

253 Full-Text Articles Assessed For Eligibility

228 Full-Text Gulf War and 229 Full-Text Afghanistan/Iraq Articles Excluded

35 Gulf War and 77 Afghanistan/Iraq articles had ineligible comparison group or case definition

156 non-Gulf study or Gulf derivative study reported elsewhere

104 non-Afghanistan/Iraq study or Afghanistan/Iraq derivative study reported elsewhere

19 Gulf War and 20 Afghanistan/Iraq treatment seeking sample

18 Gulf War and 28 Afghanistan/Iraq not original research or OR not calculable

49 Eligible Articles Reporting Psychological Disorders

25 Gulf War veterans

24 Afghanistan/Iraq War veterans

Depression

14 Gulf War

13 Afghanistan/Iraq (10 in meta-analysis)

23,533 Records Identified Through Database Search

Alcohol/Substance use

9 Gulf War


Generalised anxiety disorder

5 Gulf War

3 Afghanistan/Iraq

PTSD

20 Gulf War (18 in meta-analysis)


Figure 1: PRISMA flowchart of the systematic review of psychological disorders in Gulf War veterans, Afghanistan/Iraq War veterans, 1990-2014

27

4.2 Depression in Gulf War veterans compared to non-deployed military personnel

4.2.1 Results

The application of the inclusion and exclusion criteria yielded 201 abstracts for further review

(Figure 1). Of these, 34 were excluded based on the abstract, leaving 167 full-text titles for review.

Twenty-five articles reported on psychological disorders in Gulf War veterans; of these, 14 (1, 6-8,

29, 31, 60-67) reported depression as an outcome and met criteria for inclusion in the quantitative

synthesis. Of these 14 studies, four (1, 6, 66, 67) used structured diagnostic interviews to

determine caseness of major depressive disorder (MDD), dysthymia, or both (three of four used

the Composite International Diagnostic Interview (CIDI) with DSM-IV criteria whilst Wolfe et al.

used the Structured Clinical Interview for DSM Disorders (SCID) with DSM-IIIR criteria); seven (7,

8, 31, 60-62, 65) used depression screening tools and three (29, 63, 64) used self-reported

physician diagnosis.

Six of the 14 studies did not present adjusted ORs (6, 8, 31, 60, 61, 65). We attempted contact

with the authors to request this information; however we were unable to obtain adjusted ORs for

any of the 6 studies. Table 1 summarises these 14 studies in the order of the case definition

hierarchy given previously and within each grouping the studies were ordered by year of

publication. The same order was followed in the forest plots (Figure 2 and Figure 3).

Eight of the 14 studies received a high overall risk of bias assessment (6, 29, 60-65). None of the

four studies using structured diagnostic interviews were assessed as having a high overall risk of

bias.

Depression and major depression meta-analysis

The forest plot of the studies reporting depression (Figure 2) indicates an increased overall odds

for Gulf-deployed, compared to non-deployed military personnel, reporting depression (OR = 2.28,

95% CI 1.88-2.76). Overall heterogeneity, as indicated by I2, was high, at 75%. Stratification by

case-definition reduced the heterogeneity dramatically for the diagnostic interview subgroup (I2 =

0%) and the self-report physician diagnosis subgroup (I2 = 0%), though less dramatically for the

screening tool subgroup (I2 = 59%). The OR for the group of studies using a screening tool (OR =

2.71, 95% CI 2.23-3.31); (7, 8, 60-62, 65, 68) was higher than the OR for the groups of studies

using the diagnostic interview (OR = 1.75, 95% CI 1.47-2.01) (1, 6, 66, 67) or the self-report

physician diagnosis (OR = 1.82, 95% CI 1.49-2.24) (29, 63, 64).

The OR for the diagnostic interview subgroup indicated the odds of major depressive disorder in

Gulf-deployed, compared to non-deployed personnel, as all of the diagnostic interview studies

28

utilised DSM criteria for major depressive disorder rather than the more general overall outcome of

‘depression’.

Figure 2 Random effects meta-analysis of depression in Gulf War veterans compared to non-deployed military personnel

A meta-analysis stratified by adjustment of odds ratio (adjusted vs unadjusted) indicated little

differences on overall odds of depression between the groups (OR (adj subgroup) = 2.25, 95% CI

1.4-3.6 vs OR unadjusted subgroup = 2.57, 95% CI 2.2-3.0, forest plot not shown). Similarly, a

meta-analysis stratified by risk of bias (high vs low) indicated little differences in the overall odds of

depression between the groups (OR (high risk of bias) = 2.03, 95%CI 1.71-2.40 vs OR (low risk of

bias) = 2.30, 95% CI 1.75-3.04, forest plot not shown).

Dysthymia or chronic dysphoria meta-analysis

Five of the 14 studies summarised in Table 1 reported dysthymia (1, 6, 67) or chronic dysphoria (7,

8) as outcomes. The forest plot in Figure 3 indicates an overall odds ratio of similar magnitude to

depression; Gulf War veterans had over twice the odds of reporting dysthymia or chronic dysphoria

compared to non-deployed personnel (2.39, 95% CI 2.0-2.86). The overall heterogeneity between

studies was small (I2 = 0%). Consistent with MDD, studies utilising a diagnostic interview to

29

determine caseness (1, 6, 67) yielded an overall lower odds ratio (1.83, 95% CI 0.5-6.7) compared

to studies utilising screening tools (7, 8). The two studies utilising screening tools contributed

much greater weight to the calculation of the overall OR than the studies utilising diagnostic

interviews, due to the larger sample sizes in the studies using screening tools, although as was

also shown in Figure 2, screening tools generally produced higher odds ratios than more

methodologically rigorous structured diagnostic interviews.

Figure 3 Random effects meta-analysis of dysthymia or chronic dysphoria in Gulf War veterans compared to non-deployed military personnel

4.2.2 Key findings

Our systematic review and meta-analyses showed that Gulf War veterans were more than twice as

likely to experience depression compared with military personnel who were not deployed to the

Gulf War. The elevated odds of depression were statistically significant in 13 of the 14 studies that

were eligible to be included. This finding persisted when the meta-analysis was stratified by risk of

bias and by outcome measure. The overall odds of Gulf War veterans experiencing dysthymia or

chronic dysphoria compared to non-deployed personnel were also doubled. However, only five of

the 14 studies eligible to be included investigated dysthymia or chronic dysphoria, and three of the

five estimates were not statistically significant. In addition, two of the five studies were of chronic

dysphoria, rather than the DSM-diagnosed condition of dysthymia.

30

Table 1 Characteristics of eligible studies comparing prevalence of depression in Gulf War veterans and non-deployed military personnel

First author

Study design and study period

Sample Case definition and measure

Outcome GWV prevalence (%)

Comp group prevalence (%)

Comments and risk of bias assessment

Study samples using diagnostic interview to determine depression casenessWolfe 1999 (6)

Cross-sectional in-person structured diagnostic interview administered by trained clinicians; 1994 to 1996

Stratified random sample of two cohorts of US GW deployed veterans from New England Region (Fort Devens, FD; n = 148) and New Orleans (NO; n = 56) and a comparison group of air ambulance unit personnel deployed to Germany (G; n = 48) during the Gulf War period.

SCID non-patient edition using DSM-III-R criteria to assess current (1 month) MDD and Dysthymia prevalence

MDD 6.6 (FD) and 4.5 (NO)

0.0 Non-response bias assessed in study: yes, for demographics, health outcomesSignificant differences between respondents and non-respondents: yes, on demographics and health outcomes.Study participation rates: 62% (FD; 353 eligible); 38% (NO; 194 eligible); 85% (G; eligible numbers not reported).Psychological interview participation rates: 42% (FD), 30% (NO), 51% (G).Overall risk of bias: high

Dysthymia 3.6 (FD) and 4.8 (NO)

0.0

MDD unadjusted odds ratio combining FD and NO GWV, compared to German deployed comparison group = 6.3 (95% CI 0.4-108). Prevalence adjusted for stratification variables (health symptoms and gender).

Ikin 2004 (1)

Cross-sectional in-person structured diagnostic interview administered by trained psychologists; 2000 to 2003

All Australian GWV (n = 1381) and random sample of Navy, Army and Air force non-deployed active duty personnel (n = 1377) matched by age, gender and service type.

CIDI using DSM-IV criteria to assess post-Gulf MDD and Dysthymia prevalence

MDD 16.7 11.3 Non-response bias assessed in study: yes, for demographics, health outcomesSignificant differences between respondents and non-respondents: yes, on demographics; no on health outcomesParticipation rates: 81% GWV (1808 eligible); 57% non-GWV (2796 eligible).Psychological interview completion rates: 78% GWV; 51% non-deployed.Overall risk of bias: low

Dysthymia 0.4 0.3MDD OR = 1.6 (95% CI 1.3-2.0) adjusted for service type, rank, age, education, marital statusDysthymia OR = 1.4 (95% CI 0.3-7.2) adjusted for service type, rank, age.

Fiedler 2006

Cross-sectional telephone

Random sample (n = 967) of all US GWV and non-

CIDI-Short Form (SF) using DSM-IV

MDD 15.1 7.8 Non-response bias assessed in study: yes, for demographicsMDD OR = 2.07 (95% CI 1.50-2.85) adjusted for

31

First author






(66) structured diagnostic interview administered by trained interviewers; 2000 to 2001

deployed personnel (n = 784)

criteria to assess 12 month MDD prevalence

age, sex, rank, branch of service, duty status, education, marital status, ethnicity

Significant differences between respondents and non-respondents: yesParticipation rates: 59% GWV (1651 eligible); 51% non-deployed (1552 eligible).Psychological interview completion rate: 55% GWV; 43% non-deployed.Overall risk of bias: low

Toomey 2007 (67)

Cross-sectional in-person structured diagnostic interview, administered by trained interviewers; 1998 to 2001

Stratified random subsample of previous study (Kang 200031). US GWV (n = 1061) and non-deployed (n = 1128).

CIDI using DSM-IV criteria to assess Gulf –era onset (Jan 1991 to July 1993) MDD or Dysthymia; Current depression using BDI-II scores >13 indicating mild (14-19), moderate (17-29) and severe (30-63) depression

MDD 7.1 4.1 Non-response bias assessed in study: yes, for demographics, health outcomesSignificant differences between respondents and non-respondents: yes, on demographics; no on health outcomes.Psychological interview completion rates: 53% GWV (1996 eligible); 39% non-GWV (2883 eligible).Overall risk of bias: low

Dysthymia 0.04 0.0MDD OR = 1.81 (95% CI 1.03-3.19) adjusted for age, gender, ethnicity, education, duty type (active v reserve/guard), service branch and rank.Current depression as indicated by the BDI-II was significantly greater in GWV at the mild, moderate and severe levels compared to non-deployed personnel.

Samples using screening tools to determine depression casenessPerconte 1993 (60)

Cross-sectional in-person questionnaire administered by VAMC PTSD clinical team; study period not stated

Convenience sample of US reservists from Western Pennsylvania tri-state area GWV (n = 439), non-deployed comparison group (n = 126) and Europe-deployed group (n = 26).

BDI-I scores >10 indicating ‘minimal depression’ (common cutoff scores 32 for BDI-I are 10-18 indicating mild depression, 19-29 indicating moderate depression, 30-63 indicating severe depression)

Depression 26.9 16.7 Non-response bias assessed in study: noResponse rates: overall approximately 95% (620 eligible; denominators for GWV and non-deployed not provided)Overall risk of bias: high

Unadjusted OR = 1.84 (95% CI 1.1-3.1)

32

First author






Sutker 1993 (61)

Cross-sectional in-person questionnaire administered by VA staff; assessed 4 to 10 mths after return

Convenience sample of five US National Guard and Army Reserve Units in US state of Louisiana, with High war-zone stress (n = 110), low stress (105) and 60 non-deployed personnel

BDI-I scores >10 indicating ‘clinical depression’; war zone stress for GWV assessed using Operation Desert Storm (ODS) War-Zone Stress Exposure scale (ODS-SE)

Depression 36.0 (High Stress) and 13.0

(Low Stress)

12.0 Non-response bias assessed in study: noResponse rates: 70% GWV (306 eligible); non-GWV not providedOverall risk of bias: high

Unadjusted OR = 2.4 (95% CI 1.0-5.6)

Sutker 1995 (62)

Cross-sectional in-person questionnaire ; assessed within 1 year of their return from the Gulf region

912 US military personnel (GWV = 653, non-deployed = 259) drawn from overall sample of 1,423 Navy, Army, Air Force and Marine National Guard and Reserve Units mobilized for active duty. 511 of 1423 excluded from the analysis. Sample design not-reported.

BDI-I scores >10 indicating ‘clinical depression’

Depression 22.0 9.0 Non-response bias assessed in study: yes, for demographicsSignificant differences between respondents and excluded participants: noResponse rates: 64% overall (1423 eligible; denominators by serving gulf-war veteran status not provided)Overall risk of bias: high

Unadjusted OR = 2.9 (95% CI 1.8-4.5)

IOWA Persian Gulf Study Group 1997 (8)

Cross-sectional telephone interview; 1995 to 1996

Stratified random sample of US IOWA state Regular military (R) and National Guard/Reserve (NG/R) GWV (n = 1896) listing IOWA as home state and non-deployed personnel on active duty or activated during Gulf War (n = 1799) stratified by age, sex, ethnicity, rank and branch of service

PRIME-MD PHQ based on DSM-III-R criteria assessing 12 month symptoms of MDD and chronic dysphoria

MDD (R) 8.1 3.9 Non-response bias assessed in study: yes, for demographicsSignificant differences between respondents and non-respondents: yesResponse rates: 78% GWV (2421 eligible); 73% non-deployed (2465 eligible)Overall risk of bias: low

MDD (NG/R)

10.1 5.3

Dysphoria (R)

5.3 3.2

Dysphoria (NG/R)

8.4 4.0

MDD Combined Unadj OR = 2.1 (95% CI 1.6-2.7).Dysphoria Combined Unadj OR = 1.97 (95% CI 1.45-2.67)Prevalence rate differences adjusted for age, sex, race, branch of military and rank.

Goss Gilroy

Cross-sectional postal survey; 1997

All Canadian GWV (sea, land, air service; n = 3113)

PRIME-MD PHQ using DSM-III-R

MDD 18.9 (14.9b) 5.8 (4.9b) Non-response bias assessed in study: noChronic 10.7 (8.9b) 4.0 (4.3b)

33

First author






1998 (7) and sample of Canadian forces personnel eligible for active duty but non-deployed (n = 3439), matched on gender, age, regular/reserve status

criteria to assess current MDD and chronic dysphoria

Dysphoria (however, an assessment was made between GWV and non-deployed personnel, indicating no significant differences on demographics and confounding factors).Response rates: 73% GWV (4262 eligible); 60% non-deployed personnel (5699 eligible)Overall risk of bias: low

MDD Adjusted OR = 3.67 (95% CI 3.04-4.44) adjusted for rank and income.b = Gulf deployed with no other theatre experienceChronic Dysphoria Adjusted OR = 2.68 (95% CI 2.13-3.35) adjusted for rank , income, branch of service, age and education

Ishoy 2004 (65)

Cross-sectional in person questionnaire administered by physicians; 1997 to 1998

All Danish Gulf veterans (n = 686) and random sample of non-deployed comparison group matched on age, gender and profession (n = 231)

SCL-90-R current Depression dimension (factor scale, scores of 3+ on the depression dimension indicating depression)

Depression 11.0 3.9 Non-response bias assessed in study: no(however, an assessment was made between GWV and non-deployed personnel, indicating no significant differences on demographics but significant differences on health symptoms).Participation Rate: 84% (821 eligible) GWV; 58% non-deployed (400 potential participants)Overall risk of bias: high

Unadjusted OR = 3.0 (95% CI 1.5-6.2)

Kang 2009 (31)

Cross-sectional postal and telephone survey; 2004

Follow-up stratified random sample from previous study (Kang 200031) of US GWV (Navy, Army, Air Force, Marine; n = 6111) and non-deployed personnel frequency matched on gender, branch of service and service status (n = 3859)

PRIME-MD PHQ-9 using DSM-IV criteria to assess current MDD.

MDD 14.9 5.8 Non-response bias assessed in study: yes, on demographics, health outcome measures.Significant differences between responders and non-responders: yes, on demographics; no, on health outcomesResponse rates: 40% GWV (15,508 eligible); 27% non-deployed (14,494 eligible). Overall risk of bias: low

Unadjusted OR = 2.8 (95% CI 2.4-3.3). Adjusted RR = 2.34 (95% CI 2.03-2.70), adjusted for age, gender, race, BMI, cigarette smoking, rank, branch of service, unit component (active duty, national guard/reserve)

Samples using self-reported physician diagnosis to determine depression caseness

34

First author






Steele 2000 (29)

Cross-sectional telephone interview; 1998

Stratified random sample of US GWV residing in Kansas (n = 1545) and non-deployed comparison group (n = 435)

Self-reported physician diagnosis of depression in period from 1990 to 1998

Depression 12.0 7.0 Non-response bias assessed in study: yes, demographicsSignificant differences between responders and non-responders: yesParticipation rate: 63% overall (3,138 eligible).Response rates: 93% GWV; 88% non-deployedOverall risk of bias: high

Adjusted OR = 1.85 (95% CI 1.22-2.81) adjusted for age, sex, income and education

Gray 2002 (63)

Cross-sectional postal survey; 1997 to 1999

Sample of all US Gulf War-era Seabees (members of US Naval Mobile Construction Battalions; n = 3831) Gulf-era Seabees deployed elsewhere (n = 4933) and Gulf-era non-deployed Seabees(n = 3104)

Self-reported physician diagnosis of depression diagnosed since 1991; and in past 12 months

Depression 7.7 4.6 Non-response bias assessed in study: yes, demographics, health outcomesSignificant differences between responders and non-responders: yes, on select demographics; yes on health outcomes.Response rates:63% overall (18,945 eligible); 70% of those located participated.Overall risk of bias: high.

Adjusted OR = 1.77 (95% CI 1.41-2.27)adjusted for age, gender, active-duty/reserve status, race/ethnicity, current smoking and current alcohol use

McCauley 2002 (64)


Random sample of three groups of US Army or National Guard veterans living in five US states (OR, WA, CA, NC and GA) and 1. serving within 50km of Khamisiyah Iraqi munitions site (KHAM GWV n = 653), 2. non-Khamisiyah deployed (GWV other deployed n = 610) and 3. non-deployed personnel (n = 516)

Self-reported physician diagnosed MDD with hospitalization

MDD 1.7 0.6 Non-response bias assessed in study: yes, demographicsSignificant differences between responders and non-responders: yesResponse rates: 71% KHAM GWV; 38% non-deployedOverall risk of bias: high

Adjusted OR (deployed v non-deployed) = 5.1 (95% CI 1.5-32.1) adjusted for age, gender, race and region of residence

35

4.3 Depression in Afghanistan/Iraq War veterans compared to non-deployed military personnel

4.3.1 Results

Thirteen studies met the eligibility criteria (69-81). Of these, two papers (Cabrera 2007 (72),

Nguyen 2013 (76)) were excluded from the meta-analysis because their samples completely

overlapped with a larger sample of another included study (Hoge 2004 (74) and Wells 2010 (81),

respectively). Also, one study (Vasterling 2006) (80), only reported mean (standard error) scores

on the Center for Epidemiologic Studies Depression Scale (CES-D) scale rather than binary data

needed to calculate ORs, and so was excluded from the meta-analysis. Of the remaining ten

studies, two (Shen 2012, (78) and Wells 2010 (81)) reported adjusted ORs for subgroups (e.g.

Wells 2010 reported separate ORs for males and females). We combined subgroup ORs within

these studies so that each study contributed only one effect estimate to the meta-analysis.

Main analysis depression in Afghanistan/Iraq War veterans

Based on a random-effects meta-analysis of ten studies, there was an increased odds of

depression in deployed Afghanistan/Iraq War veterans compared with non-deployed personnel

(OR 1.58, 95% CI 1.14 to 2.17) (Figure 4). However, there was a very high amount of statistical

heterogeneity (I2 = 98%), so the meta-analytic effect should be interpreted with caution in terms of

the degree of elevated odds. Across studies, the magnitude of the ORs ranged from 0.94 to 3.08.

36

Figure 4 Random effects meta-analysis of depression in Afghanistan/Iraq War veterans compared to non-deployed military

Subgroup and sensitivity analyses depression in Afghanistan/Iraq War veterans

Sources of heterogeneity were assessed by subgroup analyses according to the outcome measure

used (ICD-9 diagnosis, screening instrument PHQ-9, or other (e.g. abbreviated screening

instrument e.g. PHQ-2)), service type of veterans (all services, National Guard only, or Air Force

only), risk of bias, and adjustment of ORs.

Stratification by type of outcome measure used to diagnose depression identified important

differences in subgroups (Figure 5). The meta-regression identified a statistically significant

difference between these three subgroups, with a relationship suggesting that the more rigorous

the outcome measure, the higher the OR (P = 0.05).

Figure 5 Random-effects meta-analysis of depression in Afghanistan/Iraq War veterans compared to non-deployed military personnel, subgrouped by type of outcome measure

37

Odds Ratio

In contrast, stratification by type of service did not reveal important differences between subgroups

(Figure 6). Results of the meta-regression suggested no statistically significant association

between type of service and magnitude of OR (P = 0.45).

Figure 6 Random-effects meta-analysis of depression in Afghanistan/Iraq War veterans compared to non-deployed military personnel, subgrouped by type of service

Stratification by risk of bias did not reveal important differences between subgroups (Figure 7).

Results of the meta-regression suggested no statistically significant association between risk of

bias and magnitude of OR (P = 0.99).

38

Figure 7 Random-effects meta-analysis of depression in Afghanistan/Iraq War veterans compared to non-deployed military personnel, subgrouped by risk of bias

Stratification by adjustment of ORs did not reveal important differences between subgroups (Figure

8). Results of the meta-regression suggested no statistically significant association between

adjustment of OR and magnitude of OR (P = 0.08).

39

Figure 8 Random-effects meta-analysis of depression in Afghanistan/Iraq War veterans compared to non-deployed military personnel, subgrouped by adjustment of odds ratios

Sensitivity analyses indicated that the overall OR did not change after excluding any individual

study, and the statistical significance did not change (Table 2). However, in all sensitivity analyses,

statistical heterogeneity remained high (i.e. I2 > 94%).

Table 2 Sensitivity analyses excluding each study one by one for studies of depression in Afghanistan/Iraq War veterans compared to non-deployed military personnel

Excluded study Pooled OR LCI 95% HCI 95% Cochran Q Chi2 P-value I2 (%)

Bray 2006 1.67 1.21 2.31 335.12 0.00 98

Bray 2009 1.65 1.18 2.32 388.84 0.00 98

Bray 2011 1.66 1.19 2.31 341.92 0.00 98

Hoge 2004 1.60 1.13 2.26 427.70 0.00 98

Hoge 2006 1.53 1.04 2.25 428.67 0.00 98

Kline 2010 1.48 1.06 2.07 429.31 0.00 98

Peterson 2010 1.54 1.09 2.17 433.11 0.00 98

Shen 2012 1.44 1.14 1.81 129.60 0.00 94

Vanderploeg 2012 1.61 1.16 2.24 432.03 0.00 98

Wells 2010 1.58 1.10 2.27 426.23 0.00 98

40

The funnel plot was not asymmetrical (Figure 9), and the Egger test was not statistically significant

(P = 0.30). (Note: FE MA, Fixed effects meta-analysis)

Figure 9 Funnel plot for the random-effects meta-analysis of depression in Afghanistan/Iraq War veterans compared to non-deployed military personnel

Comparison of summary odds ratio of depression in Gulf War veterans vs Afghanistan/Iraq War veterans

The P-value for the test for equality of the summary OR of depression in Gulf War veterans’ meta-

analysis (OR = 2.28, 95% CI 1.88-2.76; I2 75%) and summary OR of depression in

Afghanistan/Iraq War veterans’ meta-analysis (OR 1.58, 95% CI 1.14 to 2.17; I2 = 98%) was 0.055.

This is suggestive of depression in Gulf War veterans being higher than in Afghanistan/Iraq War

veterans compared with their non-deployed military comparison groups respectively, but the

difference between the two summary ORs narrowly missed statistical significance.

41

Table 3 Characteristics of eligible studies comparing prevalence of depression in Afghanistan/Iraq War veterans and non-deployed military personnel

Citation Study design and period

Sample Depression case measure and definition

Outcome Afghanistan/Iraq deployed prevalence

(%)


Comments and overall risk of bias assessment

Wells 2010 (81)

Cohort study randomly selected from all US military serving in October 2000 (Millennium Cohort Study, 1st/baseline panel 2001-3, follow up 2004-6). Internet or paper survey in 2004-06

40,219 cohort participants who completed both questionnaires and met inclusion criteria (n=55021). Exclusion criteria included indicators of depression at baseline, deployed prior to/while completing 2001-3 questionnaire, incomplete data. Participants in 1st panel who deployed to Iraq or Afghanistan Wars between questionnaire surveys with (n=225) and without (n=92) combat exposure and those who did not deploy (n=872)

PHQ defined new onset depression: (1) endorsed having depressed mood/anhedonia, and (2) responded “> half the days” or “nearly every day” to ≥5 of 9 PHQ items in past 2 weeks, suicidal ideation if present at all. Combat exposed if ≥1 specified combat experience in past 3 years

New onset depressionMales

Combat exposed 5.7Non-combat exposed 2.3

3.9 1st panel response rate was 31%, but published investigations suggest sample is representative of military personnel including deployers, reporting is reliable, response bias is minimal.Overall risk of bias: Low

Females Combat exposed 15.7Non-combat exposed 5.1

7.7

Deployed with combat exposure vs not deployed: males OR 1.32 (95% CI 1.13-1.54); females OR 2.13 (1.70-2.65) adjusted for deployment status, birth year, education, marital, smoking, alcohol, baseline PTSD symptoms/diagnosis, rank, service component and branch, occupation.Deployed without combat exposure vs not deployed: males adj OR 0.66 (0.53-0.83) females OR 0.65 (0.47-0.89).Females (n=10,178) were 25.3% of cohort sample

Kline 2010 (75)

Cross sectional anonymous self-administered survey of National Guard (NG) undergoing Iraq pre-deployment medical assessments; 2007-08

New Jersey (NJ) NG (n=2543) undergoing pre-deployment for Iraq: two groups; ≥1 prior OEF/OIF deployment since 2001 (n=625) and no prior OEF/OIF deployments (n=1910). Approx. 14.5% had served in conflicts other than OEF or OIF. De-identified Iraq pre-deployment health data on all 2995 NG from NJ Department of Military and Veterans Affairs (DMAVA)

Major depression and any depression (major depression or depression not otherwise specified) defined using PHQ-9.Prescribed use of antidepressant past 12 months

Major depression

5.1 2.0 Response rate =2665/2995 (89.0%). Sample approx. 50% of NJ NG force. NJ NG included more Hispanics, fewer non-Hispanic whites than a national NG sample, though few differences in current data on race. Depression 0.8% in DMAVA NG health assessment data vs 3.4% in study survey. Non response bias not assessed due to survey anonymityOverall risk of bias: low

Previously deployed to war in Iraq or Afghanistan vs non-OEF/OIF deployed group OR=3.07 (95% CI 1.81-5.19) adjusted for age, sex, race/ethnicity, education, income, marital status, and military deployment other than OEF/OIF.Any depression 6.6 2.3Adj OR=2.94 (95% CI 2.09-4.13)Prescribed use antidepressant

9.8 2.8

Adj OR=3.54 (95% CI 2.35-5.33)

42




(%)



Vander-ploeg 2012 (79)

Cross sectional anonymous online survey of currently active Florida NG; 2009-10

10,400 currently active Florida NG invited, 4005 responded. 3098 in final sample (1443, 46.6% deployed to Afghanistan/Iraq, 1655 not deployed)

Major depression during past month using PHQ-9 if DSM-IV criteria met and work, home or interpersonal impairment reported at ‘very difficult’ level

Major depression

3.3 1.0 Response rate 41.3%Non response bias not assessed due to survey anonymity. No information on Florida NG cohort available.Overall risk of bias: high

OR 0.94 (95% CI 0.29-3.07) adjusted for demographics, pre deployment psychological trauma or traumatic brain injury (TBI), and deployment related factors including combat, physical injuries, potentially traumatic combat experiences, blast exposure and TBI. In deployed with a single probable mild TBI OR 2.55 (95% CI 1.40-4.64) and with multiple TBIs OR 4.73 (1.61-13.89)

Shen 2012 (78)

Random sample of approximately 25% of all active duty US personnel from all services between 2001 and 2006, by combining databases (US defence and inpatient and outpatient health information from all civilian and military health providers)

678,382 US personnel from all services: 333,548 (49%) Army, 98,524 (14%) Marines, 134,015 (20%) Navy 112,295 (17%) Air Force. Deployment groupings were Afghanistan/Iraq deployed, deployed at other known locations under OIF/OEF (such as Kuwait, Qatar, Saudi Arabia, Turkey), deployed to classified or unknown locations

Enlisted persons diagnosed with major depression ICD-9 code either 296.2 or 296.3 anytime between 2001 and 2006

ICD-9 coded major depression

Did not give overall percentages for all group, gave by service type and by deployment location

Sample was representative of the US Armed Forces active duty enlisted populationOverall risk of bias: low

Peterson 2010 (77)

Cross-sectional survey post deployment of US personnel deployed to Iraq (combat zone) or Qatar (non combat zone) based on de-identified data

Participants were active duty US Air Force non combatant personnel deployed to Iraq (n=4,408) or Qatar (“non deployed” comparison group) (n=959) who completed a PDHA; 2005-2007

PHQ-2 to measure symptoms of depressed mood or anhedonia; ≥1 positive response considered screen positive for depression

Depression screen positive

9.9 5.4 Previous reports showed high completion rates for Health Assessments but response rate not reported/applicable. Demographic characteristics of groups similar in gender, age, marital, and military

OR 1.90 (95% CI 1.40-2.59). Not stated whether OR was adjusted for possible confounding factors

43




(%)



US Department of Defense (DoD) Post-Deployment Health Assessment (PDHA) surveys; 2005-2007

grade, but average time in service unavailable. Deployment length = 4m. Generalisability for other services could be limited.Overall risk of bias: high

Hoge 2004 (74)

Anonymous cross-sectional survey phase of a longitudinal study; 2003

Samples from an Army combat infantry brigade pre deployment to Iraq (n=2530); an infantry brigade of same division 6m post deployment to Afghanistan (n = 1962); an Army infantry brigade 8m post Iraq deployment (n = 894); and Marine Corp units 6m post Iraq deployment (n = 815)

Questionnaires administered 3-4m after return to US. PHQ-9 to assess major depressive disorder in past month using 2 outcome variables: broad screening definition using DSM-IV criteria; and conservative (strict) screening definition also requiring substantial functional impairment or a large number of symptoms

Depression (broad)

15.2 (Army post Iraq)14.2 (Army post Afghanistan)14.7 (Marines post Iraq)

11.4 (Army pre deployment Iraq)

Response rate: (defined as completion of any part of survey) of 98% among the 58% of combined samples available to attend study briefings

Demographic characteristics of sample similar to the general, deployed, active duty infantry population

Overall risk of bias: low

Adj OR Army post Iraq 1.40 (95% CI 1.12-1.76),Adj OR Army post Afghanistan 1.29 (1.07-1.54), adj for age, rank, education, marital, race/ethnicityUnadj OR Marines post Iraq 1.34 (1.06-1.70),vs Army pre deployment to IraqDepression (strict) 7.9 (Army post Iraq)

6.9 (Army post Afghanistan)7.1 (Marines post Iraq)


Adj OR Army post Iraq 1.53 (95% CI 1.12-2.08),Adj OR Army post Afghanistan 1.33 (1.03-1.71), adj for age, rank, education, marital, race/ethnicity,Unadj OR Marines post Iraq 1.37 (0.99-1.90)All vs Army pre deployment to Iraq

Hoge 2006 (73)

Analysis of Defence Medical Surveillance System (DMSS) database for data on all US Army soldiers and Marines who completed a routine PDHA between 1 May

Army soldiers and Marines post deployment to Iraq (n=222,620), Afghanistan (n=16,318), and other locations, e.g. Bosnia, Kosovo (n= 64,967) who completed the routine PDHA

Modified PHQ-2 measures depressed mood and anhedonia; ≥1 positive response considered screen positive for depression. Administered using electronic device or paper survey, pre deployment or within 1-2 weeks of return home. Referral for mental

PHQ-21 item

PHQ-22 items

Iraq 4.5*

Afghanistan 2.5

Iraq 1.6*

Afghanistan 1.0

1.9

0.8

Demographics of study population and study findings using survey and electronic versions of the PDHA were similar so combined. 18% of study population did not have a PDHA; similar but more likely to be active duty Marines. Some demographic differences

* Iraq deployment associated with depression compared with Afghanistan and other locations after controlling for demographics. Afghanistan deployment associated with depression compared with

44




(%)



2013 to 30 April 2004

health problem, mental health care utilisation, attrition assessed during 12m follow up period.

other location after controlling for demographic factors. OR not given in paper.

between deployment groupsOverall risk of bias: low

Shen 2012 (78)

Database analysis on several combined sources from US Defense Manpower Data Center and TRICARE, to obtain active duty personnel, demographic service, mental and related health information

678 382 unique active duty personnel serving between 2001 and 2006, approx 49% Army, 14% Marine, 20% Navy, 17% Air Force. Four groups: Not deployed under OEF/OIF; Deployed- Iraq or Afghanistan; Other known locations under OEF/OIF, e.g. Kuwait, Qatar, Turkey; Classified/ unknown locations

ICD-9 diagnosis of major depression between 2001 and 2006. Also considered 3 deployment lengths (data not shown)

ArmyMarinesNavyAir Force

5.13.85.83.5

1.71.22.23.1

Sample 25% and representative of US Armed Forces active duty population, Captured diagnoses from in/outpatient settings, civilian and military providers.Undertook sensitivity analyses. OR adj for demographic (gender, race/ethnicity, marital age) and service characteristicsOverall risk of bias: low

Army Adj OR 3.52 (95% CI 3.21-3.86)Marines Adj OR 4.51 (3.66-5.57)Navy Adj OR 3.25 (2.50, 4.22)Air Force Adj OR 1.45 (1.22, 1.72)Reference group is not deployed under OIF/OEFOEF-OIF deployed females - Army 11% Marines 3%, Navy 13%, Air Force 15% and similar to Not deployed.

Bray 2006 (69)

Cross sectional self-report anonymous DoD survey of Health Related Behaviour Among Active Duty Military Personnel (HRBS); 2006 (9th data point in series since 1980)

Sample of all eligible active duty US military personnel (excluded recruits, academy students, AWOL, or had permanent change of station). n=16,146 (3639 Army, 4627 Navy, 3356 Marine, 4524 Air Force)

40,436 US active duty service members were sampled from installations or at remote locations with 28,546 completing the surveys (5927 Army, 6637 Navy, 5117 Marine Corps, 7009 Air Force and 3856 Coast Guard), Data were weighted to represent all active duty personnel

Index of Need for Further Depression Evaluation 3-item Version A Burnam depression developed based on 2 items from CES-D and 1 item from the Diagnostic Interview Schedule based on reports of extended period of depression symptoms primarily in past 12 months

Need for Further Depression Evaluation

22.32 22.48 Overall response rate: 51.8%.Participants were selected to represent men and women in all pay grades of the active force worldwide. Data were weighted to represent all active duty personnel in the analyses.Overall risk of bias: low

Unadjusted OR 95% CI in OEF/OIF veterans vs did not serve any operation

45




(%)



Bray 2009 (70)

Cross sectional self-report anonymous Health Related Behaviour Among Active Duty Military Personnel questionnaire survey; 2008 (10th data point in series since 1980, included active duty Coast Guard for first time)

Sample of all eligible active duty US military personnel (excluded recruits, academy students, AWOL or incarcerated personnel). n=28,546; (5927 Army, 6637 Navy, 5117 Marine, 7009 Air Force, 3856 Coast Guard)

Index of Need for Further Depression Evaluation 3-item Version A Burnam depression developed based on 1 item from the CES-D and 2 items from the Diagnostic Interview Schedule based on reports of both current and extended periods of depression in past 12 months

Need for Further Depression

EvaluationAllArmyNavyMarinesAir ForceDoD ServicesCoast Guard

21.6426.2919.4225.1313.5221.63

26.86

20.4222.2921.9125.7814.0520.54

17.71

Overall response rate: 71.6%.Participants were selected to represent men and women in all pay grades of the active force worldwide. Data were weighted to represent all active duty personnel in the analyses.Overall risk of bias: low

Unadjusted OR 95% CI combat deployed in past year and ever served in OEF/OIF vs not combat deployed past year

Bray 2011(71)

Anonymous cross-sectional DoD web-based survey of Health Related Behaviour Among Active Duty Military Personnel (HRBS), 2011

Stratified random sample of all members of the Army, Navy, Marine Corps, Air Force, and Coast Guard who were non-deployed and on active duty at time of the study. Eligible sample size was 154,011 from the DoD services and 14,653 from the USCG. Stratified random sample DoD by service, gender, and pay grade, US CG by work setting (ashore, afloat, air), gender, and pay grade. Eligible respondent 34416 DoD ( Army 6,932, Navy 7,571, Marine Corps 8,339, Air Force 11,574) USCG 5461

Two questions “I felt depressed” and “I felt sad” past week scored on 5-point scale, ranging from “Never” to “5-7 days. Scores coded and categories as high/low depression level past week

High level depression past week

ArmyNavyMarinesAir ForceCGAll services

Combat deployed since Sept 11, 2001 served in OIF/OEF

47.8 (1.1)46.0 (SE 1.2)47.7 (SE 1.2)33.4 (SE 0.7)42.8 (SE 2.7)44.1 (SE 0.6)

Not combat deployed since Sept 11

39.7 (SE 1.5)40.9 (SE 1.5)50.1 (SE 1.3)29.2 (SE 0.8)31.8 (SE 1.1)38.1 (SE 0.7)

Response rate: DoD 22%, CoastGuard 37%Overall risk of bias: low

46

4.3.2 Key findings

Based on a random-effects meta-analysis, there was an increased odds of depression in

deployed Afghanistan/Iraq War veterans compared with non-deployed personnel. However,

there was a very high amount of statistical heterogeneity, so the meta-analytic effect should

be interpreted with caution in terms of the actual level of the increased odds.

Stratification by type of outcome measure used to diagnose depression identified a

statistically significant difference between these three subgroups (ICD-9, screening

instrument or other), with a relationship suggesting that the more rigorous the outcome

measure, the higher the OR. Other subgroup analyses did not identify a statistically

significant difference between subgroups and the high heterogeneity persisted.

The difference in the summary OR for depression in Gulf War veterans compared with

Afghanistan/Iraq War veterans from the meta-analyses narrowly missed statistical

significance.

47

4.4 PTSD in Gulf War veterans compared to non-deployed military personnel

4.4.1 Results

Twenty studies met the eligibility criteria (1, 6-9, 17, 29, 31, 60, 63, 64, 66, 67, 82-88). Two

studies (9, 88) reported prevalence data on the same cohort, but Unwin 1999 reported an

OR for males while Unwin 2002 reported an OR for females. We combined these gender-

specific ORs so that only one effect estimate for the Unwin studies contributed to the meta-

analysis. Three studies (8, 17, 87) reported separate ORs for regular and reservist veterans.

We included each subgroup as a separate comparison in the meta-analysis.

Main analysis

Based on a random-effects meta-analysis, there was an increased odds of PTSD in

deployed compared with non-deployed veterans (OR 3.39, 95% CI 2.79 to 4.13) (Figure 10).

There was a moderate amount of statistical heterogeneity (I2 = 53%).

48

Figure 10 Random-effects meta-analysis of PTSD in Gulf War veterans and non-deployed military personnel

Subgroup and sensitivity analyses

Sources of heterogeneity were assessed by subgroup analyses according to the outcome

measure used (structured interview versus screening instrument versus self-reported

physician diagnosis), type of service (regular versus reservist), risk of bias and adjustment of

ORs.

Stratification by type of outcome measure did not reveal important differences between

subgroups (Figure 11). Results of the meta-regression suggested no statistically significant

association between type of outcome measure and magnitude of OR (P = 0.71).

49

Odds Ratio

Figure 11 Random-effects meta-analysis of PTSD in Gulf War veterans and non-deployed military personnel, subgrouped by type of outcome measure

Stratification by regular versus reservist service did not reveal important differences between


association between type of service and magnitude of OR (P = 0.45).

Figure 12 Random-effects meta-analysis of PTSD in Gulf War veterans and non-deployed military personnel, subgrouped by type of service

50

Stratification by risk of bias revealed important differences between subgroups (Figure 13).

Results of the meta-regression suggested a larger OR in the high risk of bias studies (P =

0.003).

Figure 13 Random-effects meta-analysis of PTSD in Gulf War veterans and non-deployed military personnel, subgrouped by risk of bias

51

Stratification by adjustment of ORs did not reveal important differences between subgroups


between adjustment of OR and magnitude of OR (P = 0.25).

Figure 14 Random-effects meta-analysis of PTSD in Gulf War veterans and non-deployed military personnel, subgrouped by adjustment of odds ratios

Sensitivity analyses indicated that the overall OR did not vary after excluding any individual

study, and the statistical significance did not change (Table 4).

52

Table 4 Sensitivity analyses excluding each study one by one for studies of PTSD in Gulf War veterans compared to non-deployed military personnel


Black 2004 (regular) 3.43 2.80 4.20 42.10 0.00 55

Black 2004 (reservist) 3.51 2.87 4.29 39.61 0.00 52

Fielder 2006 3.38 2.75 4.14 42.13 0.00 55

Goss Gilroy 1998 3.40 2.75 4.20 42.28 0.00 55

Gray 2002 3.34 2.71 4.11 41.03 0.00 54

Holmes 1998 3.38 2.77 4.13 42.18 0.00 55

Ikin 2004 3.36 2.73 4.14 41.74 0.00 54

Iowa 1997 (regular) 3.42 2.79 4.19 42.20 0.00 55

Iowa 1997 (reservist) 3.47 2.84 4.24 40.84 0.00 53

Kang 2003 3.43 2.69 4.38 41.60 0.00 54

McCauley 2002 3.28 2.72 3.95 35.90 0.01 47

Murphy 2006 3.51 2.94 4.18 31.89 0.03 40

Perconte 1993 3.37 2.75 4.12 41.94 0.00 55

Pontius 1992 3.35 2.75 4.09 41.03 0.00 54

Smith 2009 3.52 2.90 4.27 37.77 0.01 50

Steele 2000 3.35 2.73 4.10 41.46 0.00 54

Stretch 1996 (regular) 3.24 2.67 3.93 35.84 0.01 47

Stretch 1996 (reservist) 3.32 2.70 4.07 40.34 0.00 53

Toomey 2007 3.31 2.71 4.05 40.14 0.00 53

Unwin 1999 3.47 2.78 4.33 41.13 0.00 54

Wolfe 1999 3.38 2.77 4.13 42.10 0.00 55

The funnel plot was not asymmetrical (Figure 15), and the Egger test was not statistically

significant (P = 0.49), indicating that publication bias was not present. (Note: FE MA, Fixed effects

meta-analysis)

53

Figure 15 Funnel plot for the random-effects meta-analysis of PTSD in Gulf War veterans and non-deployed military personnel

54

Table 5 Characteristics of eligible studies comparing prevalence of PTSD in Gulf War veterans and non-deployed military personnel

First author

Study design and period





Pontius1992 (85)

Mental health screening and outreach programs conducted by a clinical team during which a survey was completed by participants

Sample of deployed and non-deployed Army, Navy and Marine reserve units in the Western Pennsylvania, Eastern Ohio and contiguous West Virginia area following Gulf War (n=537)

Mississippi Scale for Combat Related PTSD (M-PTSD)-Revised. Cut off score ≥89

PTSD 16.15 (n=57) 2.13 (n=2) Non-response bias assessed in study: not assessed.Self-selection (non-random) of participantsOverall risk of bias: high

Study population composition: 87.5% males

Males and females included in the analysis.

Perconte 1993 (60)

Cross-sectional in-person questionnaire administered by Veterans Affairs Medical Centre (VAMC) PTSD clinical team; study period not stated

Convenience sample of US reservists (Army, Navy and Marine) from Western Pennsylvania tri-state area; GWV (n = 439), non-deployed (ND) (n = 126) and Europe-deployed (n = 26) group

M-PTSD. Cut off score ≥89

PTSD 15.53 3.97 (ND) Response rates: overall approximately 95% (620 eligible; denominators for GWV and non-deployed not provided)Non-response bias assessed in study: noSmall number of cases of PTSD in comparison groups, n=5 ND, n=1 Europe deployed, n=68 in GWVOverall risk of bias: high

88.2% of participants were males. Males and females included in the analysis.

Stretch 1996 (87)

Anonymous cross sectional postal questionnaire; no date stated

Active duty and reserve veterans from Pennsylvania and Hawaii who deployed either to the Persian Gulf as a result of ODS in the Army, Navy, Air Force and Marines or did not deploy anywhere (non-deployers)

PTSD algorithm utilising selected items from Impact of Event Scale and Brief Symptom Inventory to denote possible risk of PTSD based on DSM-III-R diagnostic criteria

PTSD (Active) 8.0 (57/715) 1.3 (21/1576) Response rate: 31% (of potential population, n=1524 deployed to Persian Gulf, non-deployed anywhere during Operation Desert Storm (n=2512)Non-response bias: Not assessedOverall risk of bias: high

PTSD (Regular)

9.2 (70/761) 2.1 (20/945)

Proportion of males and females in the sample not stated

55

First author






Wolfe 1999 (6)

Cross-sectional in-person structured diagnostic interview administered by trained clinicians; 1994-1996

Stratified random sample of two cohorts of US GW deployed veterans from New England Region (Army) (Fort Devens, FD, n = 148) and New Orleans, NO (all military branches (n = 56) and a comparison group of air ambulance unit personnel deployed to Germany (n = 48) during the Gulf War

CAPS (structured clinical interview) to assess clinical levels of PTSD

35-item M-PTSD modified for Desert Storm personnel

PTSD (current)

5.4 (FD) and 7.2 (NO)

0.0 Participation rates: 62% (FD; 353 eligible); 38% (NO; 194 eligible); 85% (Germany; not reported). Psychological interview participation rates: 42% (FD), 30% (NO), 51% (Germany)Non-response bias assessed in study: yes in both demographics and health outcomesSignificant differences between respondents and non-respondents: yes in both demographics and health outcomesOverall risk of bias: high

PTSD (lifetime)

6.5 (FD) and 8.2 (NO)

0.0

Prevalences were adjusted for stratification variables (gender and reported health symptoms).

FD - GWV 91.7% males, NO 78.8% males, and Germany 87.5% males.Males and females included in the analysis.

IOWA Persian Gulf Study Group 1997(8)


Stratified random sample of US Iowa state Regular military (R) and National Guard/Reserve (NG/Res) GWV (n = 1896) and active duty or activated non-deployed personnel (n = 1799) stratified by service, age, sex, ethnicity and rank

PTSD Checklist –Military (PCL-M). Cut-off score ≥50

PTSD (R) 1.9 0.7 Response rates: 78% GWV (2421 eligible); 73% non-deployed (2465 eligible)Non-response bias assessed in study: yes, for demographics, significant differences between responders and non-respondersOverall risk of bias: low

PTSD (NG/R) 2.0 1.1

Prevalence rate difference adjusted for age, sex, race, branch of military and rank:Total GW vs non-deployed 0.9 (95% CI -0.3, 1.5)R vs non deployed 0.9 (05% CI -0.1, 1.9)NG/R vs non-deployed 0.9 (95% CI 0.0, 1.7)

8.9% of eligible sample were female. Males and females included in the analysis

Holmes Cross sectional Air National Guard from A version of the M-PTSD 6.8 1.7 Response rate: 46% of original

56

First author






1998(82)

postal survey; 1992

one Unit members activated into the Air Force in preparation for GW (n=517) and remaining unit members not deployed and remained in US (n=497)

M-PTSD

Categorical cut off score ≥89

sample (58.5% deployed, 41.5% non-deployed)Non-response bias: assessed, higher response from deployed and from higher ranks.Overall risk of bias: high

87% participants male. Males and females included in the analysis.

Goss Gilroy 1998 (7)


All Canadian GWV (sea, land, air service; n = 3113) and comparison group sample of Canadian forces personnel eligible for active duty but ND (n = 3439), matched on gender, age, military duty (regular/reserve status)

PCL-M to assess PTSD symptoms and health care provider-diagnosed PTSD

PTSD (symptoms)

2.5a (2.1b) 1.2a (0.6b) Response rates: 73% GWV (4262 eligible); 60% non-deployed personnel (5699 eligible)Non-response bias assessed in study: noA comparison between GWV and non-deployed personnel indicated no significant differences on socio-demographic and possible confounding factors.Overall risk of bias: low

PTSD (provider diagnosed)

3.1a (2.0b) 1.4a (0.5b)

GWV vs comparison group:PTSD (symptoms) adj OR = 2.69 (95% CI 1.69-4.26) adj for incomePTSD (provider diagnosed) adj OR = 3.34 (95% CI 2.13-5.26) adj for income, service

a with other theatre experience, b with no other theatre experienceOf participants 93.9% GWV were male, 94.2% comparison group were male. Males and females included in the analysis.

Unwin 1999(9)

Cross sectional postal survey; 1997-1998

Random stratified sample of UK service personnel (Army, Navy and Royal Air Force) deployed to GW (n=2735), Bosnia (n=2393) and non-deployed Era cohort (n=2422). Stratified by service, sex, age, service status, rank and fitness (army, air force)

Symptoms of Post-Traumatic Stress Reaction (PTSR) taken from the M-PTSD

PTSR 13.2 4.7 (Bosnia)4.1 (Era)

Response rate: 65.1% (valid responses); 70.4% GW, 61.9% Bosnia, 62.9%, Era cohort.Non-response bias assessed (tracing a randomly selected sample of 100 GW, 50 Bosnia, 50 Era participants, who were non-responders after two mailings)-significant differences between responders and non-responders: (Yes, demographics (by age and

PTSR OR (GW vs Era) = 2.7 (95% CI 2.1-3.6)PTSR OR (GW vs Bosnia) = 2.3 (95% CI 1.7-3.2)

GW cohort 92.4% males, Bosnia 91.3% males, Era 92.7% males. Males only included in the analysis.

57

First author





Comments and risk of bias assessmentserving status); health outcomes: noOverall risk of bias: low

Steele 2000(29)


Stratified random sample of US Kansas resident GWV (n = 1545) and non-deployed (ND) comparison group (n = 435). Consisting of Army, Air Force, Navy, Marines and Coast Guard branches

Self-reported physician diagnosed PTSD new onset 1990-98 in period from 1990 to 1998

PTSD 6.0 1.0 Participation rate: 65% overall, and 93% GWV vs 88% non-deployed eligible participated. 15% GWV’s military records indicated they had not served in the GW but reported that they had (excluded from analyses). Small number PTSD cases in non-deployed group (n=6)Non-response bias assessed for demographics; significant differences between responders and non-responders on age, service branch, rank, sexOverall risk of bias: high

PTSD GWV vs non-deployed Adj OR = 4.74 (95% CI 2.05-10.94) adjusted for age, sex, income, education

Of participants, 86% of GWV and 87% of non-deployed group were male

Males and females included in the analysis

Gray 2002(63)

Cross-sectional postal survey; 1997 to 1999

Sample of all US Gulf War-era Seabees (members of US Naval Mobile Construction Battalions; Gulf War Seabees (n = 3,831) Seabees deployed elsewhere (DE) (n = 4,933) and non-deployed Seabees (ND) (n = 3,104)

Self-reported physician-diagnosed PTSD with onset after 1991

PTSD 3.08 0.71 (ND) 0.61 (DE)

Response rates: 68.6% overall (17,559 contacted.Non-response bias assessed in study: significant differences between responders and non-responders on select demographics and on health outcomesOverall risk of bias: high

PTSD GW Seabees vs ND Adjusted OR 4.23 (95% CI 2.59-6.92)PTSD Seabees vs Deployed elsewhere Adjusted OR = 4.27 (95% CI 2.79-6.52)

Adjusted for age, gender, active duty/reserve, status, race/ethnicity, current smoking and alcoholOf participants, 95.5% were male. Males and females included in the analysis

McCauley 2002(64)

Cross-sectional telephone survey; 1998 to 1999

Random sample of three groups of US Army or National Guard veterans living in 5 US states, and

Self-reported physician diagnosed PTSD since the Gulf War

PTSD 7.0 (KHAM) 0.8 (ND)8.7 (non-KHAM)

Response rates: 71% KHAM GWV;

Participation rates: 78% PTSD deployed v non-deployed adj OR = 14.9 (95% CI 5.6-60.9)

58

First author






1.) Serving within 50k of Khamisiyah Iraqi munitions site (KHAM GWV n=653), 2) Non-KHAM deployed (GWV other deployed n=610) and 3) Non-deployed (n=516)

PTSD KHAM v non-KHAM adj OR = 1.0 (95% CI 0.6-1.7)Adjusted for age, gender, race, region of residenceOf participants, KHAM 96.2% males, non-KHAM 93.9% males, non-deployed 89.3% malesMales and females included in the analysis

KHAM (838 eligible), 75% non-KHAM (809 eligible), 38% non-deployed (741 eligible).Non-response bias was assessed in the study for demographics, health outcomes; significant differences between responders and non-responders. Sample was not representative of troops serving in the Gulf WarOverall risk of bias: high

Kang 2003(83)

Cohort postal/telephone survey as Phase 1 of the longitudinal National Health Survey of Gulf War era veterans and their Families; 1995-1996

Stratified random sample of US GV (n=11,441) and non-deployed (n=9476). Stratified by gender (females, n=3000), unit component (active, research and national guard) (NG=4000, reservists=5000) and branch (Army, Navy, Air force and Marine Corps)

PTSD Checklist (PCL) to assess current prevalence of PTSD, cut-off score ≥ 50

PTSD (cohort) 12.1 4.3 Participation rate: 70% overall (76.3% GWV vs 63.2% non-GWV) eligible in-state and contactable.Non-response bias assessed for demographics; significant differences between responders and non-responders on age, race, marital status and rankOverall risk of bias: low

PTSD (population)

10.1 4.2

PTSD in GWV vs non deployed adj OR = 3.1 (95% CI 2.7-3.4) adj for gender, age, marital, rank and unit component.Population rate accounted for complex sample survey design unadjusted OR 2.6 (95% CI 2.2-3.0)

GWV 81.4%, non-deployed 78.1% malesMales and females included in the analysis

Ikin 2004(1)

Cross-sectional in-person structured diagnostic interview admin-istered by trained psychologists; 2000 to 2002

All Australian GWV (n = 1381) and random sample of Navy, Army and Air force ND active duty personnel (n = 1377) matched by age, gender and service type

CIDI using DSM-IV criteria to assess prevalence PTSD first present post-Gulf War

PTSD 5.4 1.4 Participation rates: 81% GWV (1808 eligible); 57% non-GWV (2796 eligible).Non-response bias assessed in study: yes, for demographics, health outcomesSignificant differences between respondents and non-respondents: yes, on demographics; no on health

PTSD adj OR = 3.9 (95% CI 2.3-6.5) adjusted for service type, rank, age, education, marital status

Males only included in the analysis

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First author





Comments and risk of bias assessmentoutcomesPsychological interview completion rates: 97% GWV; 89% non-deployedOverall risk of bias: low

Black 2004(17)

Cross-sectional structured telephone interview; 1995-1996

Random sample selected from US Iowa GWV; regular military (Reg) (n = 985), GW National Guard (NG)/Reserve (Res) (n = 911), non-GW regular military (n = 968), and non-GW NG/Res (n = 831)

PTSD Checklist (PCL) to assess current (past month); cut-off score of ≥ 50

PTSD (reg) 1.9 0.7 Participation rate: 91%, 76% (of eligible participants n=4886)Non response bias was not assessed. Limited to Iowans, limited power to detected differences between racial groupsSignificant differences between responders and non responders: not assessed.Limitations include Recall bias, sensitised by media/medical professionalsOverall risk of bias: Low

PTSD (NG/Res

2.0 1.1

PTSD (total) 1.9 0.8

Prevalences were weighted to account for complex study design.PTSD OR in Gulf War veterans vs non-deployedReg: OR 2.6 (95% 1.19-6.2)NG/Res OR 1.9 (1.0-3.5)Total: OR 2.5 (95% CI 1.2-5.0)adjusted for age, gender, race, rank, branch, military status, and prior mental health conditionProportion of females in sample not reported.Participation in combat was related to PTSD OR =2.1 (95% CI 1.7-4.2)

Fiedler 2006(66)

Cross-sectional telephone structured diagnostic interview administered by trained interviewers; 2000 to 2001

Random sample (n = 967) of all US GWV and non-deployed personnel (era veterans) (n = 784) including Army, Navy, Air Force, Marines and Coast Guard

12-month version of CIDI for the DSM-IV criteria to assess PTSD

PTSD (total) 3.4 0.9 Response rates: 59% GWV (1651 eligible); 51% non-deployed (1552 eligible).Non-response bias assessed in study: yes, for demographicsSignificant differences between respondents and non-respondents: yesAdj OR presented for anxiety disorders but not for PTSD separately in paperOverall risk of bias: low

PTSD (males) 3.4 0.7

PTSD (females)

4.0 2.2

GWV 92% males. Era veterans 88% males

Toomey 2007

Cross-sectional in-person

Stratified random subsample of previous

PTSD diagnosis using CAPS, a

PTSD diagnosis

6.2 1.1 Participation and Psychological interview completion rates:

60

First author






(67) structured diagnostic interview, administered by trained interviewers; 1998 to 2001

study (68)

US GWV (n = 1061) and non-deployed (n = 1128).

structured interview, to DSM-IV criteria, for Gulf –era onset (Jan 1991 to July 1993) PTSD

Current PTSD symptom severity assessed using a 17-item PTSD checklist rated on scale of 1-5

53% GWV (1996 eligible); 39% non-GWV (2883 eligible)Non-response bias assessed in study: yes, for demographics, health outcomesSignificant differences between respondents and non-respondents: yes, on demographics; no on health outcomesOverall risk of bias: low

PTSD Checklist caseness (≥50)

9.8 2.7

PTSD Checklist mean score (SE)

27.5 (0.6) 22.8 (0.4)

PTSD diagnosis adj OR = 5.78 (95% CI 2.62-12.74) adjusted for age, gender, ethnicity, duty type (active v reserve/guard), service branch and rank.Current PTSD checklist caseness adj OR 3.84 (95% CI 2.16-6.80) adjusted for age, gender, education, ethnicity, duty type, service branch and rankPTSD checklist mean score was significantly greater in GWV compared to non-deployed personnelMales and females included in the analysisDeployed and non-deployed groups 78% males

Murphy 2006(84)

Cross-sectional postal survey. A study to develop and evaluate screening questionnaires in the military, without framing of Gulf War deployment context; 2001

Stratified random sample of UK Armed forces services (Army, Navy, RAF) by service and size of unit, 45 individuals randomly selected from each unit. GWV status was determined by record linkage. GWV (n = 308), non-GWV (n = 1339)

PTSD Checklist (PCL-C), cut-off ≥50 on full 17 item PCL-C or ≥40 on abridged 14 item PCL-C version. Full and abridged survey questionnaires tested in both study groups

PTSD 1.0 1.9 Participation rate: overall approximately 57% (out of 2873 in original sampling frame were linked on GWV status)Non-response bias not assessedComparison between groups displayed differences on service with larger proportion of Army, fewer Navy and RAFOverall risk of bias: low

PTSD Adjusted OR = 0.42 (95% CI 0.12-1.42) adjusted for length of questionnaire (where data from both questionnaires was available), age, gender, rank, service

GWV 99.4% males, non-GWV95.2% males. Males and females included in the analysis

Kang 2009(31)

Cross-sectional postal and telephone survey; 2004

Follow-up stratified random sample from previous study (68) of US GWV (Navy, Army, Air Force, Marines; n = 6111) and non-deployed Gulf Era personnel frequency

PCL-C to assess current symptom severity of PTSD in past 4 weeks; cut-off score of ≥ 50

PTSD 15.2 4.6 Response rates: overall 34%; 40% GWV (15,508 eligible); 27% Gulf Era (14,494 eligible).Non-response bias assessed for demographics, health outcomes; significant differences between

61

First author






matched on gender, service branch and status (n = 3859)

responders and non-responders on demographics but not on health outcomesOverall risk of bias: lowAdjusted Risk Ratio (RR) = 2.98 (95% CI 2.54-3.50),

adjusted for age, gender, race, BMI, current smoking, rank, service branch, unit component (active duty/NG/guard/ reserve)Of participants, 79.9% GWV and 78.2% Gulf Era were males. Males and females included in the analysis

Smith 2009(86)

Baseline survey of US Millennium cohort Study; 2001-2003

75,156 baseline consenting participants of Millennium Cohort Study (enrolled July 2001 to June 2003) consisting of Army, Air Force, Navy/Coast Guard and Marine Corp.

Classified by deployment: none prior; 1991 GW only; 1991 GW and Bosnia/Kosovo/Southwest Asia; and Only Bosnia/Kosovo/Southwest Asia

PCL-C assessed current symptoms: cut-off ≥50 and ≥1 intrusion, ≥3 avoidance and ≥2 hyperarousal symptoms.Self-report measure assessed PTSD diagnosis: ever being told by their doctor or other health professional that they have PTSD (no, yes); if yes, what year did problem begin?

PTSD diagnosis, without current symptoms

18.3 59.4 Response rate: 71% (participation in follow up survey); 36% (to initial response to the participation)

No differences in responder health with respect to medical encounters

Differential response rates that are influenced by PTSD results

Potential response bias to continued follow-up is ongoing

Use of survey instrument as a surrogate for PTSD diagnosis and can only measure PTSD in a populationOverall risk of bias: low

PTSD symptoms without diagnosis

9.7 64.0

PTSD diagnosis with current symptoms

23.6 58.9

Comparisons in GW only and None prior: Weighted percent (above)PTSD diagnosis without current symptoms adj OR = 1.46 (95% CI 0.90-2.36)PTSD symptoms without diagnosis adj OR = 0.79 (95% CI 0.55-1.13)PTSD diagnosis with current symptoms adj OR = 1.33 (95% CI 0.59-2.99)

Weighted percent and OR adjusted for gender, birth year, education, marital status, race/ethnicity, military rank and component

Millennium Cohort participants 73.2% males. Males and females included in the analysis

62

4.4.2 Key findings

Eighteen studies were eligible for inclusion in the meta-analysis of PTSD in Gulf War

veterans. Pooled analysis based on random-effects model indicated that PTSD was over

three times more likely in Gulf War veterans compared with non-deployed military personnel.

There was moderate statistical heterogeneity between studies. Sources of heterogeneity

were assessed by subgroup analyses according to the outcome measure used, and

stratification by type of outcome measure used, duty status, risk of bias and adjustment of

OR did not reveal important differences between subgroups, but the summary OR of PTSD

in Gulf War veterans was higher in studies assessed as overall high risk of bias compared

with those with low risk of bias.

63

4.5 PTSD in Afghanistan/Iraq War veterans compared to non-deployed military personnel

4.5.1 Results

Eighteen studies met the eligibility criteria (3, 69-71, 73-75, 77, 79, 80, 89-96). Of these,

three studies (Fear, 2010, Hotopf, 2006, Jones, 2013) (3, 90, 92) had completely

overlapping samples so we only included the data for Fear et al. (3) in the meta-analysis.

Four studies (Fear 2010, Shen 2010, Smith 2008, Vasterling 2006) (3, 80, 94, 95) reported

separate ORs for different services (e.g. for regular and reservist veterans, or for Army, Navy

and Air Force veterans). In the main analysis we combined these within-study ORs so that

only one effect estimate per study contributed to the meta-analysis.

Main analysis

Based on a random-effects meta-analysis, there was an increased odds of PTSD in

deployed veterans compared with non-deployed personnel (OR 2.12, 95% CI 1.65 to 2.72)

(Figure 16). However, there was a very high amount of statistical heterogeneity (I2 = 97%),

so the meta-analytic effect should be interpreted with caution in terms of the actual level of

the increased odds.

64

Figure 16 Random-effects meta-analysis of PTSD in Afghanistan/Iraq War veterans and non-deployed military personnel

Subgroup and sensitivity analyses

Sources of heterogeneity were assessed by subgroup analyses according to the outcome

measure used (structured interview versus screening instrument), type of service (regular

versus reservist), risk of bias and adjustment of ORs.

Stratification by type of outcome measure did not reveal important differences between


association between type of outcome measure and magnitude of OR (P = 0.82).

Figure 17 Random-effects meta-analysis of PTSD in Afghanistan/Iraq War veterans and non-deployed military personnel, subgrouped by type of outcome measure

65

Stratification by regular versus reservist service did not reveal important differences between


association between type of service and magnitude of OR (P = 0.88).

Figure 18 Random-effects meta-analysis of PTSD in Afghanistan/Iraq War veterans and non-deployed military personnel, subgrouped by type of service

Stratification by risk of bias did not reveal important differences between subgroups (Figure

19). Results of the meta-regression suggested no statistically significant association

between risk of bias and magnitude of OR (P = 0.62).

66

Figure 19 Random-effects meta-analysis of PTSD in Afghanistan/Iraq War veterans and non-deployed military personnel, subgrouped by risk of bias

Stratification by adjustment of ORs did not reveal important differences between subgroups


between adjustment of OR and magnitude of OR (P = 0.84).

67

Figure 20 Random-effects meta-analysis of PTSD in Afghanistan/Iraq War veterans and non-deployed military personnel, subgrouped by adjustment of odds ratios

Sensitivity analyses indicated that the overall OR did not vary after excluding any individual

study, and the statistical significance and heterogeneity did not change (Table 6).

68

Table 6 Sensitivity analyses excluding each study one by one for studies of PTSD in Afghanistan/Iraq War veterans compared to non-deployed military personnel

Excluded study Pooled ES LCI 95% HCI 95% Cochran Q Chi2 P-value I2 (%)

Barlas 2011 2.18 1.70 2.79 450.90 0.00 97

Bleir 2011 2.12 1.63 2.74 512.02 0.00 97

Bray 2006 2.21 1.72 2.84 466.71 0.00 97

Bray 2009 2.17 1.69 2.78 452.65 0.00 97

Fear 2010 2.20 1.71 2.83 480.55 0.00 97

Hoge 2004 2.16 1.67 2.77 456.89 0.00 97

Hoge 2006 1.99 1.56 2.53 266.92 0.00 95

Hourani 2007 2.11 1.63 2.73 517.15 0.00 97

Kline 2010 2.04 1.57 2.64 520.47 0.00 97

Peterson 2010 2.03 1.57 2.61 518.96 0.00 97

Shen 2009 2.02 1.47 2.79 519.22 0.00 97

Shen 2010 2.11 1.62 2.74 492.42 0.00 97

Smith 2008 2.04 1.55 2.67 520.64 0.00 97

Vanderploeg 2012 2.23 1.73 2.86 506.99 0.00 97

Vasterling 2006 2.21 1.71 2.84 495.76 0.00 97

Wittchen 2012 2.10 1.63 2.71 520.26 0.00 97

The funnel plot was asymmetrical (Figure 21), and the Egger test was statistically significant (P =

0.003), which suggests that small studies had systematically different ORs to larger studies. (Note:

FE MA, Fixed effects meta-analysis)

Figure 21 Funnel plot for the random-effects meta-analysis of PTSD in Afghanistan/Iraq War veterans and non-deployed military personnel

69

Comparison of summary odds ratio of PTSD in Gulf War veterans vs Afghanistan/Iraq War veterans

The 95% CI for the OR of PTSD in Gulf War veterans (OR 3.39, 95% CI 2.79 to 4.13) and

Afghanistan/Iraq War veterans (OR 2.12, 95% CI 1.65 to 2.72) did not overlap. The P-value for the

test for equality of the summary OR of PTSD in Gulf War veterans’ meta-analysis and summary

OR of PTSD in Afghanistan/Iraq War veterans’ meta-analysis was 0.004, indicating that the

summary OR of PTSD in Gulf War veterans was statistically significantly higher.

70

Table 7 Characteristics of eligible studies comparing prevalence of PTSD in Afghanistan/Iraq War veterans and non-deployed military personnel

First-named author

Study design, study period

Sample PTSD case definn, measure

Outcome Prevalence (%)



Shen 2009(93)

Retrospective database analysis; data on US sailors deployed overseas 2002-2006, including Defense Manpower Data Center and Post-Deployment Health Assessment (PDHA) survey data

Sailors deployed in a variety of overseas locations (n=112,720), including Iraq, Afghanistan, other ground deployments, with deployed on a ship as reference category

4-item PDHA survey to assess positive screening for PTSD, cut-off ≥2 items

PTSD Iraq 10.0 - Participation rate: High PDHA completion for Afghanistan/Iraq deployed but sailors on routine ship operation exempted. Iraq/ Afghanistan deployed more likely male and middle ranked sailors vs those on ships. PDHA administered soon after deployment, may not fully capture PTSD not manifested. Possible underreporting because stigmaOverall risk of bias: high

PTSD Afghan 5.0 -

PTSD Other - 3.0

PTSD Ship - 3.0

Models presented for effect of deployment location on probability of screening positive for PTSD but no ORIn participants, overall 88% males, Iraq 92% males, Afghanistan 93% males Other 86% males, Ship 88% males. Males and females included in the analysis

Wittchen, 2012(96)

Cross sectional study; 2010-2011

Stratified random sample German soldiers deployed in Afghanistan (n=1483), and comparison not deployed overseas (n=889)

Computer assisted Munich CIDI-M (military) interview by psychologist to assess PTSD to DSM-IV criteria, 12 month prevalence, 12 month incidence, lifetime prevalence

12 month diagnosis

2.9 1.2 Participation rate: 92.8% deployed, 95.4% non-deployed.Non response bias not assessed, but study group assessed representative of German armed forces deployed to AfghanistanOverall risk of bias: low

12 month incidence

0.9 0.2

Lifetime diagnosis

4.6 2.7

12 month diagnosis OR = 2.5 (95% CI 1.1-5.6)12 m incidence OR = 4.2 (95% CI 0.7-24.5)Lifetime prevalence OR = 1.7 (95% CI 0.96-3.1)Prevalences were weightedDeployed 94.8%, non-deployed 95.5% males. Males and females included in analysis

Kline, 2010(75)

Cross sectional anonymous self-administered survey pre-deployment to Iraq: 2007-08

New Jersey (NJ) National Guard (NG) members (n=2543): ≥1 prior OEF/OIF deployment since 2001 (n=625) and No prior OEF/OIF deployments (n=1910)

PTSD Checklist (PCL): cut-off ≥50 (more restrictive) and symptom cluster method based on DSM-IV (less restrictive)

PTSD (PCL) 14.0 4.2 Participation rate: 95% overall.Non response bias not assessed due to survey anonymity. NJ NG similar to national NG sample on some demographics and PTSD, but included greater proportion of Hispanics, fewer non-Hispanic whites, though few differences in current data on raceOverall risk of bias: low

PTSD (DSM –IV)

21.1 9.0

PTSD (PCL) OR = 3.69 (95% CI 2.59-5.24)PTSD (DSM – IV) OR =2.70 (95% CI 2.05-3.55) adjusted for age, sex, race/ethnicity, education, income, marital status and military deployment other than in OEF or OIF

Of participants, deployed 85.5% males, non-deployed 89.0% males. Males and females included in the analysis

71

First-named author






Vanderploeg; 2012(79)

Cross sectional anonymous online survey; 2009-10

Current active members of Florida NG deployed to OEF/OIF (n=1443) and not deployed (n=1655)

PCL-C, cut-off score ≥50 and reported very difficult or greater to function at work, home or get along with others

Probable PTSD

6.9 1.9 Participation rate: 41.3%Non response bias not assessed due to survey anonymity No information on Florida NG cohort available.Overall risk of bias: high

PTSD OR = 0.40 (95% CI 0.13-1.23) adjusted for other covariates, demographic, pre-deployment factorsOf participants, deployed 87.4% males, non-deployed 79.2% males. Males and females included in analysis.

Shen, 2010(94)

Database analysis on several combined sources from US Defense Manpower Data Center and TRICARE, to obtain active duty personnel, demographic service, mental and related health information

Active duty enlisted personnel serving b/n 2001 and 2006 (n=678,227); deployed to Afghanistan/Iraq, not deployed to Afghanistan/Iraq, deployed other OEF/OIF missions (eg Kuwait, Qatar)

ICD-9 coded clinical diagnosis of PTSD any time 2001 to 2006

PTSDArmyMarinesNavyAir Force

4.413.516.461.34

0.630.520.830.62

Sample 25% and representative of US Armed Forces active duty population, Captured diagnoses from those still in service, may have missed severe cases diagnosed within VA system, though this not likely to be biased by deploymentOverall risk of bias: low

PTSD Deployed vs not deployed Iraq/ Afghanistan based last deployment locationArmy adj OR 3.96, Marines OR 4.57, Navy adj OR 9.06, Air Force adj OR 1.25

PTSD Deployed other OEF/OIF missions vs not deployed Afghanistan/IraqArmy adj OR 3.97, Marines adj OR 3.51, Navy adj OR 0.54, Air Force adj OR 0.36adj for service, demographic characteristicsPersonnel included 84.1% (Air Force) to 96.3% (Marines) males. Males and females included in analysis

Bleier 2011(89)

Analysis of cross-sectional surveys of Australian personnel deployed to Solomon Islands, East Timor or Bougainville and military comparison groups; 2007-2008

Personnel who deployed at least twice; reported they deployed at least once to Iraq/ Afghanistan and East Timor (n=771) and never deployed (n=573)

PCL-C; cut-off ≥30 PTSD 28.0 20.0 Participation rate overall for surveys: 44%Data analyses limited to those with adequate complete deployment data. Non-response bias assessed: ex-serving and enlisted people under-represented in responders.PCL-C cut-off of ≥30 considered of clinical relevance, top quartile for combined dataset, because of relevance of subsyndromal PTSDOverall risk of bias: low

PTSD deployed at least twice (including Iraq/ Afghanistan and East Timor) vs never deployed adj OR 2.1 (95% CI 1.5-2.8) adj for age, sex, rank, current serving status

Of participants, 92% at least twice deployed, 84% never deployed males. Males and females included in analyses

Peterson, Cross-sectional Active duty US Air Post-Development PTSD 4.1 0.7 Previous reports showed high

72

First-named author






2010(77)

survey post deployment of US personnel deployed to Iraq or Qatar based on de-identified data from US DoD PDHA surveys; 2005-2007

Force personnel deployed to Iraq (combat zone) (n=4,408) or Qatar ((non combat zone, ‘non deployed’ comparison group) (n=959) who completed a PDHA

Health Assessment (a 4-item measure to screen for PTSD in primary care, PC-PTSD Screen), score ≥2 positive screen for PTSD, score ≥3 higher threshold risk

positive screen

completion rates for Health Assessments but response rate not reported/applicable. Demographic characteristics of groups similar in gender, age, marital, and military grade, but average time in service unavailable. Deployment length = 4m. Generalisability for other services could be limitedOverall risk of bias: high

PTSD higher threshold risk

2.1 0.4

PTSD positive screen OR = 5.86 (95% CI 2.66-13.62).PTSD higher threshold risk OR = 5.00 (95% CI 1.78-16.12).Upper limits of 95% CI noted not accurate by Cornfield method. Adjustment factors not stated.Deployed to Iraq 85.4% males, deployed to Qatar 83.9% males. Males and females included in the analysis.

Hourani 2007 (91)

Cross-sectional, self-report questionnaire survey; 2006

Sample of all eligible US reserve and NG military personnel comprising army, navy, marine, air force reserve and coast guard. Served in OEF/OIF (n = 5325), non-deployed (n = 4886)

PCL-C past 30 days, cut off ≥50 considered need for further evaluation of PTSDDeployment status based on served in OEF or OIF, did not serve in theatres

PTSD 10.5 (SE 1.2) 4.9 (SE 0.7) Overall response rate: 51.8%. Nonresponse adjustment to help compensate for potential bias of nonsurveyed persons. Survey targeted to US reserve and NG personnel rather than military overall. Responses anonymous, so likely minimised non reporting biasOverall risk of bias: low

Adjusted prevalences (SE). Adjusted estimates were standardised to correct for differences in the demographic distributions between the theater of operations groups. Main effects of Reserve component, gender, age group, enlisted/officer status, marital status, education, and race/ethnicity were used in this standardisation process

Bray 2006 (69)

Cross sectional self-report anonymous DoD survey of Health Related Behaviour Among Active Duty Military Personnel (HRBS); 2006

Sample all eligible active duty US military personnel. n=16,146 (3639 Army, 4627 Navy, 3356 Marine, 4524 Air Force). 40,436 US active duty service members were sampled with 28,546 completing the surveys (5927 Army, 6637 Navy, 5117 Marine

PCL-C past 30 days, cut off ≥50 considered need for further evaluation of PTSDDeployment status based on served in OEF or OIF, did not serve in theatres

PTSD 7.1 (0.6) 6.1 (0.6) Overall response rate: 51.8%Participants were selected to represent men and women in all pay grades of the active force worldwide. Data were weighted to represent all active duty personnel in the analysesOverall risk of bias: low

Adjusted prevalences (SE). Adjusted estimates were standardised to correct for differences in the demographic distributions between the theater of operations groups. Gender, age group, enlisted/officer status, marital status, education, and race/ethnicity were used in this standardisation process

73

First-named author






Crops, 7009 Air Force and 3856 Coast Guard)

Bray 2009 (70)

Cross sectional self-report anonymous Health Related Behaviour Among Active Duty Military Personnel questionnaire survey; 2008 (10th data point since 1980, included Coast Guard for first time)

Sample of all eligible active duty US military personnel (excluded recruits, academy students, AWOL or incarcerated personnel). n=28,546; (5927 Army, 6637 Navy, 5117 Marine, 7009 Air Force, 3856 Coast Guard)

PCL-C past 30 days, cut off ≥50 considered need for further evaluation of PTSDDeployment status based on combat deployed and served in OIF or OEF or Not combat deployed since Sept 11, 2001

PTSDAllArmyNavyMarinesAir ForceDoD ServicesCoast Guard

12.4 (SE 0.8)16.4 (SE 1.5)8.9 (SE 0.6)16.5 (SE 2.3)5.5 (SE 0.6)12.4 (SE 0.8)

10.7 (SE 2.9)

8.2 (SE 0.4)9.0 (SE 1.0)8.2 (SE 0.7)13.0 (SE 1.2)5.3 (SE 0.4)8.4 (SE 0.4)

5.9 (SE 0.5)

Overall response rate: 71.6%Participants were selected to represent men and women in all pay grades of the active force worldwide. Data were weighted to represent all active duty personnel in the analysesOverall risk of bias: low

Barlas 2011 (71)

Anonymous cross-sectional DoD web-based survey of Health Related Behaviour Among Active Duty Military Personnel (HRBS), 2011

Stratified random sample all 154,011 eligible members US Army, Navy, Marine Corps, Air Force, and 14,653 Coast Guard non-deployed and on active duty at time of study. 34,416 DoD respondents (Army 6,932, Navy 7,571, Marine Corps 8,339, Air Force 11,574); 5,461 USCG

4-items about feeling very upset when reminded of a stressful experience, emotional numbness/lack of loving feelings for close persons, difficulty concentrating, feeling jumpy/ easily startled, on a 1-5 Likert scale. Total score ≥4 = “high PTS” level past 30 days. Deployment status -combat deployed and served in OIF, OEF or New Dawn, Not combat deployed since Sept 11, 2001

PTSDAllArmyNavyMarinesAir ForceCoast Guard

5.9 (SE 0.3)8.6 (SE 0.6)3.6 (SE 0.5)6.7 (SE 0.6)2.3 (SE 0.2)3.5 (SE 1.0)

4.0 (SE 0.3)4.5 (SE 0.7)4.7 (SE 0.7)7.4 (SE 0.7)1.6 (SE 0.2)1.9 (SE 0.3)

Response rate: DoD 22%, Coast Guard 37%Survey designed to be a statistically-valid selection of a representative sample of service members. Data were weighted to represent all active duty personnel in the analysesOverall risk of bias: low

Hotopf 2006 Cohort study Stratified random PCL-C cut-off ≥50, PTSD (PCL-C)

4.0 3.7 Participation rates: 62.3% deployed

74

First-named author






(90) self-report questionnaire; 2004-06

sample of UK armed forces personnel deployed to Iraq Jan to April 2003 (Op TELIC 1) (n=4722, 3936 regulars, 786 reservists) and UK armed forces personnel at the time but not deployed to TELIC 1 (Era) (n=5550, 4750 regular, 800 reservists).

and also a definition requiring the participant scored moderate or above on one of the re-experiencing symptoms, three avoidance symptoms, andtwo hyperarousal symptoms

Regular 56.3% non-deployed samples

Non-response bias assessed via intensive follow up study, late responder analysis, sensitivity analysis, healthy warrior effect considered – unlikely important difference missedOverall risk of bias: low

Reservists 6.0 2.8PTSD (alternate definition)

4.0 3.0

PTSD OP Telic vs Era Regulars Adj OR 1.17 (95% CI 0.92–1.48)Reservists Adj OR 6.95 (95% CI 0.89–54.2)Interaction for deployment by regular/reservist status for PTSD (p=0.02)PTSD OP Telic vs Era Regulars adj OR 1.00 (0.79–1.28) after reassigning Era participants to Iraq War group if they had served in subsequent TELIC 1 deploymentPTSD (alternative definition) OR 1.21 (95% CI 0.96–1.53)OR adj for age, sex, rank, educational and marital status, service branch, and fitness to deployTELIC 1 sample 92% males, Era 90% males. Males and females included in analyses

Hoge et al 2004 (74)

Anonymous cross-sectional survey phase of a longitudinal study; 2003

Samples from an Army combat infantry brigade pre deployment to Iraq (n=2530); an infantry brigade of same division 6m post deployment to Afghanistan (n = 1962); an Army infantry brigade 8m post Iraq deployment (n = 894); and Marine Corp units 6m post Iraq deployment (n = 815)

Questionnaires administered 3-4m after return to US. PCL. Results scored positive if ≥1 intrusion, 3 avoidance, 2 hyperarousal symptoms categorised as moderate level. For the strict definition to be met, score had to be ≥50

PTSD (broad)



Response rate: (defined as completion of any part of survey) of 98% among the 58% of combined samples available to attend study briefings

Demographic characteristics of sample similar to the general, deployed, active duty infantry populationOverall risk of bias: low

Adj OR Army post Iraq 2.13 (95% CI 1.71–2.66)Adj OR Army post Afghanistan 1.25 (95% CI 1.03–1.52)Adj OR Marines post Iraq 2.40 (95% CI 1.92–2.99)All vs Army pre deployment to Iraq, adj for age, rank, education, marital, race/ethnicityPTSD (strict)



Adj OR Army post Iraq 2.84 (95% CI 2.17–3.72)Adj OR Army post Afghanistan 1.26 (95% CI 0.97–1.64)Adj OR Marines post Iraq 2.66 (95% CI 2.01–3.51)All vs Army pre deployment to Iraq, adj for age, rank, education, marital, race/ethnicity

75

First-named author






Of participants, males ≥98% across services

Hoge et al 2006 (73)

Analysis of Defence Medical Surveillance System (DMSS) database on all US Army soldiers and Marines who completed a Post Deployment Health Assessment; May 2003 to April 2004

Army soldiers and Marines post deployment to Iraq (n=222,620), Afghanistan (n=16,318), and other locations, e.g. Bosnia, Kosovo (n= 64,967) who completed the routine PDHA

4-item PTSD screen (Primary care-PTSD screen or “PCPTSD”). 4 questions cover key domains of PTSD: re-experiencing trauma,numbing, avoidance, and hyperarousal. Cut-off ≥2/4 items at risk of PTSD. Deployment locations - OEF, OIF or other (Bosnia, Turkey, Uzbekistan, Kosovo, on a ship, or other)

PTSD OIF 9.8%OEF 4.7%

2.1 % Demographics of study population and study findings using survey and electronic versions of the PDHA were similar so combined. 18% of study population did not have a PDHA were similar to those who had a PDHA by deployment location and demographics but were somewhat more likely to be active duty Marines. Some demographic differences between deployment groupsOverall risk of bias: low

Adj OR OIF vs other 5.51 (95% CI 5.20-5.83)Adj OR OEF vs other 2.52 (95% CI 2.30-2.76)OR adjusted for sex, age, marital, service branch, component, grade

Of participants, OIF males (89.4)%, OEF males (91.3), other (88.6)

Vasterling, 2010(97)

Prospective pre and post deployment cohort survey

US Army deployed soldiers (n=774, regular active duty n=670, NG n=104), non-deployed (regular active duty n=309). Pre and post deployment assessment

PCL-C according to DSM-IV-TR, cut-off score ≥50

PTSD post deploymentRegularNG

12.014.0

11.0

Participation rate: 94% at time 1, 73% at time 2

Participants at Time 1 generally reflected US Army population but females and officers underrepresented. Sample not population based, only included one service branch. NG sample does not generalise to broader reservistsOverall risk of bias: low

Of participants, deployed 92.9% males and non-deployed 90.3% males. Males and females included in the analysis.

No OR included for PCL caseness, and therefore no adjustment for possible confounding factors. Study’s main outcome of interest was pre to post deployment change in PTSD severity by PCL-C score.

Smith, 2008(95)

Prospective cohort analysis at follow up in 2004-06; baseline 2001-03

Millennium cohort study participants – active duty and Reserve/NG personnel; (n=50,184 for analysis) (n=50128) deployed (n=11952) and non-deployed

PCL-C.Sensitive definition of symptoms of PTSD used DSM-IV criteria alone

Specific definition included DSM-IV criteria and cut-off ≥50

Persisting symptoms by sensitive criteria

47.9 (deployed with combat exposures)22.4(deployed without combat exposures)

45.9(Non deployed)

Participation rate in follow up: 71%

Analyses have previously suggested a representative sample of military personnel by demographic and health outcomes, shown minimal reporting biases, and on differences in methods of completing surveyOverall risk of bias: low

New onset symptoms by sensitive criteria

8.7(deployed with combat exposures)2.1(deployed without combat exposures)

3.0(Non deployed)

76

First-named author






(n=38176) Self-reported having been told by their doctor or other health professional that they have PTSD (‘ever’ at baseline, ‘past 3 years’ at follow up)

Persisting symptoms by specific criteria

43.5(deployed with combat exposures)26.2(deployed without combat exposures)

47.6(Non deployed)

New onset symptoms by specific criteria

4.3 (overall)7.6(deployed with combat exposures)1.4(deployed without combat exposures)

2.3(Non deployed)

PTSD specific definition deployed with combat exposures vs not deployedArmy adj OR 3.59 (95% CI 3.08-4.17)Air Force adj OR 3.38 (95% CI 2.29-4.98)Navy/CG adj OR 2.48 (95% CI 1.48-4.14)Marine adj OR 2.78 (95% CI 1.52-5.07)Deployed without combat exposures vs not deployed Air Force adj OR 0.56 (95% CI 0.3-0.89) Other comparisons not significant.OR adjusted for baseline characteristics including sex, age, education, marital status, race/ethnicity, rank, service component, occupation, smoking, and problem alcohol drinking.Of participants, deployed 81.4% males and non-deployed 69.6% males. Males and females included in the analysis.

Fear, 2010(3)

Cohort study survey; 2007-09. Multiple phase study- 2004-06 sample was reassessed and 2 new samples added

Randomly sampled UK armed forces (n=9990, reg regulars, 8278, res, reservists, 1712). Included Iraq cohort (90) and personnel deployed Afghanistan (April 06-07), and joined UK armed forces since 2003;

PCL C, cut-off ≥50 PTSDI only

4.8 4.0 Participation rate: 56% (of eligible sample)Non-response bias assessed: no association between mental health at phase 1 in and responding phase 2 in Iraq cohort. Analyses considered response weightsOverall risk of bias: low

PTSDA only

3.4 4.0

PTSD Both I and A 2.7 4.0Regulars PTSD I/A

4.2 4.0Reservists PTSD I/A

5.0 1.8PTSD deployed I only vs not deployed I/A adj OR = 1.20 (95% CI 0.87-1.67)PTSD A only vs not deployed I/A adj OR = 0.93 (95% CI 0.54-1.59)PTSD Both I/A vs not deployed I/A adj OR = 0.92

77

First-named author






deployed Iraq only (I) (n=4203), Afghanistan only (A) (n=1123), Iraq and Afghan-istan (I and A) (n=1389), Not deployed Afghanistan/Iraq (n=3255)

(95% CI 0.58-1.46)PTSD Regulars deployed I/A vs not deployed I/A adj OR = 1.13 (95% CI 0.82-1.54)PTSD Reservists deployed I/A vs not deployed I/A adj OR = 2.83 (95% CI 1.23-6.51)

OR adjusted for age, sex, marital status, educational status, rank, serving status, service.

Of participants, deployed to I only 90.6% males, A only 94.5% males, I and A 94.3% males, not deployed I/A 86.8% males. Males and females included in the analysis.

78

4.5.2 Key findings

Sixteen studies were eligible for inclusion in the meta-analysis of PTSD in Afghanistan/Iraq War

veterans. Pooled analysis based on a random-effects model indicated that PTSD was just over

twice as likely in Afghanistan/Iraq War veterans compared with non-deployed military personnel.

However there was high heterogeneity between studies and the level of the elevated odds of the

summary meta-analysis effect estimate should be interpreted with caution. Sources of

heterogeneity were assessed by subgroup analyses. Stratification according to the outcome

measure used (structured interview versus screening instrument), type of service (regular versus

reservist), risk of bias and adjustment of ORs did not reveal important differences between

subgroups and the high level of heterogeneity persisted. Gulf War veterans had a higher odds of

PTSD than the Afghanistan/Iraq War veterans relative to their non-deployed comparison groups.

79

4.6 Alcohol use and substance use disorders in Gulf War and Afghanistan/Iraq War veterans compared to non-deployed military personnel

4.6.1 Results

Of the 25 primary studies identified in relation to psychological disorders in Gulf War veterans

(Figure 1), nine studies (1, 7, 8, 29, 31, 64, 66, 67, 84) were included in the meta-analysis in

relation to alcohol use and substance use disorders in Gulf War veterans. Of the 24 primary

Afghanistan/Iraq War veteran studies identified, nine studies reported on alcohol/substance use

disorders and seven discrete studies were included in the meta-analysis. The characteristics of

these studies are reported in Table 8 and Table 9. Across the Gulf War studies, sample sizes

ranged from 308 to 6111 for Gulf War veterans and 482 to 3859 for the non-deployed personnel.

Across the Afghanistan/Iraq War veteran studies, other than the anonymous surveys or database

analyses, sample sizes ranged from 625 to 11,171 for Afghanistan/Iraq War veterans and 889 to

37,310 for non-deployed personnel. The percentage of female veterans in these studies was low.

It ranged from 0.6% to 22% for Gulf War veterans and 2.5% to 22% for the non-deployed military

comparison groups, and 3% to 21% for Afghanistan/Iraq War veterans and 4% to 55% for the non-

deployed military comparison groups.

The studies included Gulf War veteran cohorts from the US, UK, Australia and Canada, in all three

services (Navy, Army, and Air Force). The military comparison groups in all the studies were

described and defined as non-deployed, i.e. not deployed to the Gulf War or Afghanistan/Iraq War

during the period of operations, rather than other conflict/other deployed personnel e.g. Germany,

Bosnia. The Afghanistan/Iraq War veteran study populations were from the US, UK and Germany.

Some of the Afghanistan/Iraq War veteran studies considered associations between levels of

combat exposure and health outcomes within the deployed group, but the primary comparisons in

the meta-analysis are between the deployed and non-deployed group.

Of the Gulf War studies, three used structured diagnostic interviews to determine the caseness of

alcohol/substance use disorders (1, 66, 67) and four used screening tools (7, 8, 31, 84). The other

two studies (29, 64) used self-reported physician diagnosis. Of the seven studies for the outcome

of alcohol use disorders, three studies provided data for adjusted OR in the published article (1, 67,

84) and the study by Kang et al. (31) provided a Relative Risk, for which the unadjusted Relative

Risk was converted to an unadjusted OR with 95% CI. Other studies provided usable data in the

published article for calculation of an unadjusted OR (7, 8, 66). Of the three studies included in the

meta-analysis for the outcome of substance use disorders, two studies provided data for adjusted

80

OR (1, 67) and the remaining study provided usable data for calculation of an OR. Another two

studies (29, 64) provided data on alcohol or drug use disorders combined which was difficult to

separate; thus, they were not included in the meta-analysis of individual outcomes but were

included in the analysis of any substance use disorder outcome.

Of the Afghanistan/Iraq War veteran studies, one used a structured diagnostic interview to

determine alcohol/substance use disorder caseness (98), and the remaining eight studies used

screening tools. Hotopf et al. (90) provided informative data on UK veterans but the study

population formed part of the cohort of a later study of UK veterans (3) which was included in the

meta-analysis. Bray et al. (69, 70) provided on request more precise estimates of standard errors

of prevalence to enable us to calculate ORs.

Gulf War veteran studies - Alcohol use disorders

The overall OR using the random effects model (46, 47) for the seven included studies was 1.33

(95% CI: 1.22, 1.46) which indicated higher risk of alcohol use disorders in Gulf War veterans

compared to non-deployed military personnel. Overall heterogeneity for all studies represented by

I2 was 14% (Figure 22). Stratification by caseness indicated that the screening tool subgroup (OR

= 1.30, 95% CI: 1.14, 1.48) and the structured diagnostic interview subgroup (OR = 1.45, 95%:

1.17, 1.81) had comparatively similar ORs, and meta-regression indicated no statistically

significant association with caseness (p=0.452). However, heterogeneity was higher in the

subgroup of studies using screening tools (I2 = 46% versus I2 = 0%). The screening tool subgroup

contributed much greater weight in calculating the overall OR than the studies using diagnostic

interviews. There were no studies in the self-reported physician diagnosis subgroup for this

outcome.

Figure 22 Random-effects meta-analysis illustrating log-transformed odds ratios of alcohol use disorders in Gulf War veterans and non-deployed military personnel

81

The studies were further stratified based on adjusted versus unadjusted OR estimates, and the OR

in both subgroups were comparatively similar (adjusted subgroup OR = 1.38, 95% CI: 1.10, 1.74;

unadjusted subgroup OR = 1.31, 95% CI: 1.17, 1.49; results of meta-regression indicated no

statistically significant association with type of OR (p=0.815). Sensitivity analyses indicated that

the overall OR did not vary after excluding any individual study for this outcome, and the statistical

significance did not change. The funnel plot was visually inspected and it did not show an obvious

lack of symmetry, and the Egger test was not statistically significant (p=0.134).

Gulf War veteran studies – Substance use disorders

Three studies (1, 66, 67) reported a substance use disorder outcome separately and the overall

OR using random effects model for these studies was 2.13 (95% CI: 0.96, 4.72; I2 = 29%). The

result was not statistically significant. Sensitivity analysis indicated, after excluding the study by

Fiedler et al. (66), that the overall OR decreased to 1.80 (95% CI: 1.09, 2.98) with overall

heterogeneity reduced (I2 = 0%) and that this finding was statistically significant. The study by

Fiedler et al. (66) had only one subject in the Era veterans’ category for the substance use

disorders outcome, and this was the reason for excluding it in the sensitivity analyses. All studies

used structured diagnostic interviews to define caseness in substance use disorders. Stratification

of studies reporting a substance use disorder outcome in Gulf War veterans was not possible due

to the small number of studies.

Gulf War veteran studies - Any substance use disorder

Many included studies in this review reported dependence or abuse for more than one substance

(including alcohol) (1, 66, 67) and some reported OR for (combined) any substance use disorders

(29, 64), which prompted us to analyse these studies for the outcome of ‘any substance use

disorder’. The overall OR for the nine studies using random effects model for any substance use

disorder was 1.35 (95% CI: 1.25, 1.46) which was statistically significant and had low

heterogeneity of I2 = 0%, indicating a higher risk of any substance use disorders in Gulf War

veterans compared to non-deployed military personnel (Figure 23). Sensitivity analyses indicated

that the overall estimate did not change after excluding any individual study. The OR remained

statistically significant throughout these analyses. No asymmetry was detected in the funnel plot

and the Egger test was not statistically significant (p=0.863).

82

Figure 23 Random-effects meta-analysis illustrating log-transformed odds ratios of any substance use disorders in Gulf War veterans and non-deployed military personnel

Gulf War veteran studies - Risk of bias of included studies

All studies were assessed for overall risk of bias. Two (29, 64) of the nine studies received a high

overall risk of bias assessment. None of the seven studies included in the alcohol use disorder

outcome analysis were assessed as having a high overall risk of bias. The summary estimates for

any substance use disorders were further analysed based on studies having an overall low or high

risk of bias (42). The OR of any substance use disorder was 1.60 (95% CI: 0.96, 2.68) for the high

risk of bias subgroup and 1.34 (95% CI: 1.22, 1.47) for the low risk of bias subgroup. Meta-

regression indicated no statistically significant association with study risk of bias (p=0.516).

Afghanistan/Iraq War veteran studies - Alcohol use disorders

For the outcome, alcohol use disorders, the overall OR using the random effects model was 1.36

(95% CI: 1.11, 1.66) which indicated higher risk of alcohol use disorders in Afghanistan/Iraq War

veterans compared to non-deployed military personnel. Overall heterogeneity for all studies

represented by I2 was 77% (Figure 24). The studies were stratified according to duty status of

personnel (regular versus reservist) and the OR in the reservist subgroup was slightly higher

(regular subgroup OR = 1.32, 95% CI: 1.04, 1.68; reservist subgroup OR = 1.58, 95% CI: 1.31,

1.91) although results of meta-regression indicated no statistically significant association with duty

status of personnel (p=0.599). Stratification by adjusted versus unadjusted OR estimates also did

not identify important differences between subgroups (adjusted subgroup OR = 1.29, 95% CI: 1.02,

1.62; unadjusted subgroup OR = 1.66, 95% CI: 1.31, 2.09); results of meta-regression indicated no

statistically significant association with type of OR (p=0.348). Stratification by caseness was not

83

possible because all studies except one used a screening tool. Sensitivity analyses indicated that

the overall OR did not vary after excluding any individual study for this outcome, and the statistical

significance did not change. When meta-analysis was restricted to studies at low risk of bias, there

was no important change to the OR (OR = 1.45, 95% CI: 1.23, 1.72). The funnel plot was not

asymmetrical, and the Egger test was not statistically significant (p=0.338).

Figure 24 Random-effects meta-analysis illustrating log-transformed odds ratios of alcohol use disorders in Afghanistan/Iraq War veterans and non-deployed military personnel

Afghanistan/Iraq War veteran studies –Substance use disorders

For the outcome, substance use disorders, the overall OR using random effects model was 1.14

(95% CI: 1.04, 1.25), which indicated higher risk of substance use disorders in Afghanistan/Iraq

War veterans compared to non-deployed military personnel (Figure 25). There was no statistical

heterogeneity (I2 = 0%), so subgroup analyses were not necessary. Sensitivity analyses indicated

that the overall OR did not vary after excluding any individual study for this outcome, and the

statistical significance did not change. We could not perform a sensitivity analyses based on study

risk of bias as all studies were rated at low risk of bias. The funnel plot was symmetrical and the

Egger test was not statistically significant (p=0.476).

84

Figure 25 Random-effects meta-analysis illustrating log-transformed odds ratios of substance use disorders in Afghanistan/Iraq War veterans and non-deployed military personnel

Afghanistan/Iraq War veteran studies - Any substance use disorder

Shen 2012 (78) was the only study that measured an ‘any substance use’ outcome in

Afghanistan/Iraq War veterans, and combining these results with the alcohol use or substance use

disorder results of other studies produced a meta-analysis with very high heterogeneity (I2 = 98%),

which we were unable to explain with subgroup analyses (duty status of personnel (regular versus

reservist), adjusted versus unadjusted subgroup, structured diagnostic interview versus screening

tool for identifying caseness, sensitivity analyses, or risk of bias) (data not shown). Therefore, we

considered it more appropriate to report the results of Shen et al. (78) separately. Shen et al. (78)

found a higher risk of any substance use disorder in Army (OR 4.05, 95% CI: 3.82, 4.30), Marine,

(OR 4.36, 95% CI: 3.82, 4.97), Navy (OR 1.77, 95% CI: 1.45, 2.16) and Air Force (OR 1.76, 95%

CI: 1.56, 1.99) veterans of the Afghanistan/Iraq Wars compared to non-deployed military

personnel.

Comparison of summary odds ratio of alcohol use disorders and substance use disorders in Gulf War veterans versus Afghanistan/Iraq War veterans

Results of meta-regressions suggested that there was no statistically significant association

between theatre of war and the OR for alcohol use (p=0.862) and narrowly missed statistical

significance for the OR for substance use disorders (p=0.053).

85

Table 8 Characteristics of eligible studies comparing prevalence of alcohol/substance use disorders in Gulf War veterans and non-deployed military personnelAuthor Year (Reference)

Study design; study period

Sample Alcohol / substance use case defn measure

Outcome GWV prevalence

(%)

Comp group prevalence

(%)

Effect measure 95% Confidence Interval

Participation rates, Assessment of overall risk of bias

IOWA Persian Gulf Study Group 1997 (8)

Cross-sectional telephone interview; 1995-96

Random sample of US Iowa state Regular military (R) and National Guard/Reserve (NG/Res) GWV (n = 1896) and active duty or activated non-deployed personnel (n = 1799) stratified by service, age, sex, ethnicity and rank

CAGE screening questionnaire assessing symptoms of alcohol abuse

Symptoms of alcohol abuse (R)

17.0 12.2Prevalence difference in all subjects

2.4 0.4, 4.5Participation rates: 78% GWV (2421 eligible); 73% non-GWV (2465 eligible), 75.5% of males (4453 eligible), 77.4% of females (433 eligible) completed the interviews of all GWV and non-GWV.Non-response bias was assessed for demographics; significant differences between responders and non-respondersEffect estimate (Prevalence difference ) was adjusted for age, sex, race, branch of military and rankOverall risk of bias: low

Symptoms of alcohol abuse (NG/Res)

19.4 16.8Prevalence difference (R) 2.3 -0.8, 5.4

Prevalence difference (NG/Res)

2.6 -0.1, 5.3

ORa (all subjects)(males and females)

1.33 1.11, 1.58

Goss Gilroy 1998 (7)


All Canadian GWV (sea, land, air service; n = 3113) and sample of Canadian forces personnel eligible for active duty but non-deployed (n = 3439), matched on gender, age, regular/ reserve status

Defined by alcohol use in past month and ≥1 positive response in CAGE and of 5 questions on consequences of alcohol drinking in past 6 months

Symptoms suggestive of alcohol abuse

9.6(SD= 0.5)b

8.5(SD= 0.6)b

ORa

(males and females)

1.14 0.97, 1.35Participation rates: 73% GWV (4262 eligible); 60% non-GWV (5699 eligible)Non-response bias not assessed. A comparison between GWV and non-deployed personnel indicated no significant differences on socio-demographic and possible confounding factors.Adjusted prevalence ORs for symptoms suggestive of alcohol abuse were not reported.Overall risk of bias: low

GWV 93.9% males and 6.1% females (n=3113), non-GWV 94.2% males and 5.8% females (n=3439)

Steele 2000 (29)

Cross-sectional

Stratified random sample

Self-reported physician

Alcohol or drug 3.0 2.0

adj OR (males and females) 1.47 0.65, 3.31

Participation rate: 65% overall (of 3,138 original

86

Author Year (Reference)




(%)


(%)



telephone interview; 1998

of US GWV residing in Kansas (n = 1548) and non-deployed comparison group (n = 482)

diagnosed alcohol or drug dependence new onset 1990-98 in males and females

dependence sample) and 93% GWV vs 88% non-GWV eligible in-state and contactable. 15% GWV’s military records indicated they had not served in the GW but reported that they had (excluded from analyses).Non-response bias assessed for demographics; significant differences between responders and non-responders on age, service branch, rank, sex.Effect estimate adjusted for age, sex, income and education levelOverall risk of bias: high

GWV 86% males and 14 % females (n=1548), non-GWV 87% males and 13% females (n=482)

McCauley 2002 (64)


Random sample of 3 groups of US Army or NG veterans living in 5 states and 1.) Serving within 50k of Khamisiyah Iraqi munitions site (KHAM GWV n=653), 2) Non-KHAM deployed (GWV other deployed n=610) and 3) Non-deployed (n=516)

Self-reported physician diagnosed alcohol or substance abuse diagnosed since the Gulf War

Alcohol or substance abuse

4.1(KHAM-deployed)3.6(non-KHAM deployed)

2.1 adj OR (KHAMnon-KHAM deployed combined) (males and females)

1.7 0.9, 3.4Participation rates: 78% KHAM GWV (838 eligible); 70% non-GWV (741 eligible)Non-response bias was assessed in the study for demographics, health outcomes; significant differences between responders and non-respondersEffect estimate adj for age, gender, race and region of residenceOverall risk of bias: high

Non-deployed group 89.3% males and 10.7% females (n=516), deployed group (KHAM and non-KHAM combined ) 95.1% males and 4.9% females (n=1263)

Ikin 2004 (1) Cross-sectional in-person structured diagnostic

All Australian male GWV (n=1381) and random sample of non-deployed

CIDI using DSM-IV criteria to assess 12-month

Alcohol dependence / abuse

19.8 12.6adj OR (males) 1.5 1.2, 2.0 Participation rates: 81%

of 1808 eligible GWV; 57% non-deployed (2796 eligible). Psychological interview: 78% GWV;

Drug 3.7 1.8 adj OR (males) 1.9 1.1, 3.2

87





(%)


(%)



interview administered by trained psychologists; 2000-02

active duty personnel (n = 1377) matched by age, gender and service (Navy, Army, Air Force)

prevalence substance use disorder first present post-Gulf War in males

dependence / abuse

51% non-deployed. Participation bias assessed for demographics and health outcomes: significant differences between responders and non-responders on demographics but not on health outcomes.OR were adj for service, rank, age, education and marital status.Overall risk of bias: low

Any substance use disorder

20.8 13.1 adj OR (males) 1.5 1.2, 2.0

GWV 98% males and 2% females (n=1871), non-GWV 97.5% males and 2.5% females (n=2924)

Fiedler 2006 (66)

Cross-sectional telephone structured diagnostic interview administered by trained interviewers; 2000-01

Random sample of all US GWV (n = 967) and non-deployed era personnel (n = 784)

CIDI-Short Form using DSM-IV criteria. 12-month prevalence in males and females

Alcohol dependence 4.6 3.1

ORa (males and females)

1.51 0.91, 2.49 Participation rates: 59% GWV (1651 eligible); 51% Era non-deployed (1552 eligible). Non-response bias assessed for demographics; significant differences, with increased Whites and NCOs responding.OR for alcohol use or drug dependence were not adjusted. OR for combined alcohol/drug dependence in GWV or Era non-deployed deployed to a conflict in addition to or other than the GW; OR 1.91 (1.04, 3.54) were adj for rank, branch, sex, marital, and education.Overall risk of bias: low

Drug dependence 1.2 0.1


9.84 1.28, 75.83

Any dependence

5.1 3.2 ORa,c (males and females)

1.62 0.99, 2.64

GWV 92% males and 8% females (n=967), Era veterans 88% males and 12% females (n=784)

Murphy 2006 (84)

Cross-sectional postal survey, not framed in

Stratified random sample of UK Armed forces services (Army, Navy,

AUDIT questionnaire. Q1 and Q2 modified to include a

Alcohol use disorders 7.4 6.6


0.95 0.46, 1.94 Participation rate: overall approximately 57% (out of 2873 in original sampling frame were linked on GWV status)

88





(%)


(%)



context of Gulf War deployment rather of a study to develop and evaluate screening questionnaires in the military2001

RAF) by service and size of unit, 45 individuals randomly selected from each unit. GWV status determined by record linkage. GWV (n = 308), non-GWV (n=1339)

higher category of units consumed

Non-response bias not assessed. Comparison between GWV and non-GW personnel indicated significant differences on service with greater proportion of Army, fewer Navy and RAF and slightly greater proportion males in the GWV groupEffect estimate adj for age, gender, rank, and serviceOverall risk of bias: low

GWV 99.4% males and 0.6% females (n=1339), NGW 95.2% males and 4.8% females (n=308)

Toomey 2007 (67)

Cross-sectional in-person structured diagnostic interview, by trained interviewers; 1998-2001

Stratified random subsample of US GWV (Navy, Army, Air Force, Marines (n = 1061) and non-deployed personnel (n = 1128) from a previous 1995 study

CIDI using DSM-IV criteria to assess substance dependence of Gulf War-era onset (1991-93)

Alcohol dependence 4.3 3.0

adj OR (males and females)

1.05 0.51, 2.16 Participation rates: 53% GWV (1996 eligible); 39% non-deployed (2883 eligible)Non-response bias was assessed. Significant differences on demographics but not health outcomesOR adj for age, gender, ethnicity, education, duty status (active vs reserve/guard), service, rank (illicit substance not adj for age or rank)Overall risk of bias: low

Illicit substance dependence

0.9 0.6adj OR (males and females)

1.20 0.27, 5.39

Any substance dependence 7.9 4.8

adj OR (males and females)

1.25 0.73, 2.16

Deployed 78% males and 22% females (n=1061), non-deployed 78% males and 22% females (n=1128)

Kang 2009 (31)

Cross-sectional postal and telephone

Follow-up stratified random sample from previous study

PHQ-9 criteria to assess probable alcohol abuse

Probable alcohol abuse 16.4 12.0

adj RRd (males and females) 1.24 1.11, 1.37

Participation rates: 40% GWV (15,508 eligible); 27% non-GWV (14,494 eligible).

89





(%)


(%)



survey; 2004 of US GWV (Navy, Army, Air Force, Marines; n = 6111) and non-deployed Gulf Era personnel frequency matched on gender, service branch and status (n = 3859)

in past 6 months

Non-response bias assessed for demographics, health outcomes; significant differences between responders and non-responders on demographics but not on health outcomesEffect estimate adj for age, gender, race, BMI, current smoking, rank, service branch, unit component (active duty, national guard/reserve)Overall risk of bias: low

GWV 79.9% males and 20.1% females (n=6111), Era veterans 78.2% males and 21.8% females (n=3859)

AUDIT, World Health Organization Alcohol use disorder identification test (99); BMI, Body Mass Index; CAGE,CAGE Questionnaire (100); CIDI, World Health Organization Composite

International Diagnostic Interview (38); CIDI –SF, World Health Organization Composite International Diagnostic Interview Short Form (101); GW, Gulf War; GWV, Gulf War veterans;

NCO, Non-commissioned officer; NG, National Guard ; NG/Res, National Guard/Reserve; Non-deployed /non-GWV, a military comparison group who were not deployed to the Gulf War

during the period of operations. OR, Odds Ratio; PRIME-MD PHQ, Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (102); R, Regular military; RR, Relative Risk;

SD, Standard Deviationa Unadjusted OR - calculated in Meta-XL (58), using reported prevalence and sample sizes for GWV and non-deployed personnel.b With no other theatre experience, defined as areas where Canadian Forces personnel served during past 12 years as part of a UN deployment.c Combined adjusted alcohol/drug dependence OR were only given for either GWV or non-GWV deployed to a conflict in addition to or other than the GW.d The unadjusted effect estimate was converted to an unadjusted OR in the meta-analysis.

90

Table 9 Characteristics of eligible studies comparing prevalence of alcohol/substance use disorders in Afghanistan/Iraq War veterans and non-deployed military personnel

First Author Year (Ref)

Study design study period

Sample Alcohol / substance use case definition / measure

Outcome Iraq/ Afghanistan veteran prevalence (%)

Comparison group prevalence (%)


Comments and assessment of overall risk of bias

Bray 2006 (69)

Cross sectional self-report anonymous questionnaire survey; 2006 (9th data point in series since 1980)

Sample of all eligible active duty US military personnel (excluded recruits, academy students, AWOL, or had permanent change of station). n=16,146 (3639 Army, 4627 Navy, 3356 Marine, 4524 Air Force)

AUDIT score >=20 assessed possible alcohol dependence. Questions assessed heavy alcohol use (≥5 drinks same occasion on ≥once/week past 30 days); any illicit drug use (past year)

Served in OEF/OIF vs non-deployed any operation- last 3 years: Alcohol dependence

3.52 2.29 Unadj OR 1.54a

1.1, 2.14 Overall response rate: 51.8%.Participants were selected to represent men and women in all pay grades of the active force worldwide. Data were weighted to represent all active duty personnel in the analyses.Overall risk of bias: low

Heavy alcohol use

19.4 16.69 Unadj 1.20 1.00, 1.45

Illicit drug use- Army

14.53 13.57 Unadj 1.09a 0.89, 1.33

Illicit drug use- Marine

11.58 8.87 Unadj 1.33a 0.93, 1.9

Illicit drug use- Navy

11.61 8.12 Unadj 1.52a 0.57, 3.46

Illicit drug use-Air Force

6.63 6.81 Unadj 0.97a 0.56, 1.62

Bray 2009 (70)

Cross sectional self-report anonymous questionnaire survey; 2008 (10th data point in series since 1980, included active duty Coast Guard for first time)

Sample of all eligible active duty US military personnel (excluded recruits, academy students, AWOL or incarcerated personnel). n=28,546; (5927 Army, 6637 Navy, 5117 Marine, 7009 Air Force, 3856

AUDIT score >=20 assessed possible alcohol dependence. Questions assessed heavy alcohol use (≥5 drinks same occasion on ≥once/week past 30 days); any illicit drug use (past year)

Combat deployed since Sept 11 2001 and served in OEF/OIF vs Not combat deployed since Sept 11 2001- Possible alcohol dependence past year

4.75 2.73 Unadj 1.78a 1.28, 2.45 Overall response rate: 71.6%.Participants were selected to represent men and women in all pay grades of the active force worldwide. Data were weighted to represent all active duty personnel in the analyses.Overall risk of bias: low

Heavy alcohol use

24.71 17.12 Unadj OR 1.58 1.26, 1.98

Illicit drug use- 28.14 24.88 Unadj OR 1.18a 0.91, 1.54

91








Coast Guard). ArmyIllicit drug use- Marine

24.07 20.84 Unadj OR 1.20a 0.93, 1.54

Illicit drug use- Navy

19.67 16.93 Unadj OR 1.20a 0.95, 1.53

Illicit drug use-Air Force

15.5 13.62 Unadj OR 1.16a 0.93, 1.45

Hotopf 2006 (90)

Cohort study self-report questionnaire; 2004-06

Stratified random sample of UK armed forces personnel deployed to Iraq Jan to April 2003 (Op TELIC 1) (n=4722, 3936 regulars, 786 reservists) and UK armed forces personnel at the time but not deployed to TELIC 1 (Era) (n=5550, 4750 regular, 800 reservists).

AUDIT to assess alcohol consumption and harmful use.Case defined as males with a score >13, females >10

Original TELIC 1 cohort AUDIT case

25.6 21.1 Adj OR 1.10Unadj 1.28

0.991.17

1.221.41

Participation rates: 62.3% deployed, 56.3% non-deployed samples.Non-response bias assessed via intensive follow up study, late responder analysis, sensitivity analysis, healthy warrior effect considered – unlikely important difference missed.OR adjusted for age, sex, rank, educational and marital status, service branch, fitness to deploy (and reservist status in regular vs reservist comparisons and take account of sampling weights).Overall risk of bias: low

Regulars 27.0 22.4 Adj OR 1.10 0.98 1.22Reservists 17.9 13.7 Adj OR 0.80 0.44 1.44

Iraq War vs Era AUDIT casea

27.0 21.2 adj OR 1.09a

Unadj OR 1.370.971.24

1.221.52

Combat vs non combat regulars in Iraq War group only

33.2 24.6 Adj OR 1.19Unadj OR 1.52

1.011.32

1.411.76

TELIC 1 sample 8% females, Era 10% females. Males and females included in analyses.No interaction by regular/reservist status (p=0.7) for AUDIT casenessaDistribution of main outcomes after reassigning Era participants to Iraq War group if they had served in subsequent TELIC 1 deployment.

Jacobson 2008 (103)

Follow up questionnaire survey of US Millennium

US Millennium Cohort Study participants who completed both

Patient Health Questionnaire (PHQ) assessed new onset alcohol

Active Duty OEF/OIF deployed with combat

4.8 3.6 Adj OR 1.03a 0.85 1.26 Follow-up response rate: 71.4%.Previous evaluations of possible biases indicate

92








Cohort Study; participants at baseline 2001-03 (n=77,047) and follow up2004-06 (n=55,021)

time point surveys and first deployment to Iraq or Afghanistan completed between baseline and follow up. 48,481 in analysis (Active duty=26,613; Reserve/NG=21,868). Of these, Deployed with (n=5510) or without (n=5661) combat. Non-deployed n=37310)

related problems (≥1 item). CAGE assessed alcohol dependence. Heavy drinking (males >14, females >7 drinks/week in previous week. Binge drinking (males ≥5, females ≥4 drinks on ≥1 day previous week or ≥5 drinks on ≥1 day/ occasion past year.

exposure vs non-deployed- PHQ Alcohol problems

cohort is representative sample military personnel, by demographic, mental health, health and exposure reporting. OR adj for sex, birth year, race/ethnicity, service, deployment length, history of mental disorders, smoking, service component, history potential alcohol dependence.

Overall risk of bias: low

Heavy weekly drinking

6.0 4.8 Adj OR 1.12 0.94 1.33

Binge drinking 26.6 19.3 Adj OR 1.31 1.14 1.49Reserve/Guard OEF/OIF deployed with combat vs non-deployed- PHQ Alcohol problems

7.1 3.8 Adj OR 1.63a 1.33 2.01

Heavy weekly drinking

8.8 5.1 Adj 1.63 1.36 1.96

Binge drinking 25.6 17.1 Adj OR 1.46 1.24 1.71Follow up survey respondents: deployed with combat exposure 8.1% males and 4.5% females, deployed without combat exposure 8.0% males and 5.5% females, and non-deployed 46.0% males and 55.1% females

Kline 2010 (75)

Cross sectional anonymous self-administered pre-deployment survey; 2007-08

New Jersey (NJ) National Guard (NG) members (n=2543) undergoing pre-deployment for Iraq: Two groups; ≥1 prior OEF or OIF deployment since 2001 (n=625) and No prior OEF/OIF deployments (n=1910).

Alcohol use measures based on questions/ algorithms in DSM-IV- based National Household Survey of Drug Use and Health. One measure of illicit drug use.

Alcohol dependence last 12 months

9.0 6.6 adj OR 1.88a 1.31, 2.69 Participation rate: 95% overall (of 2665 in original study popn)Non response bias not assessed due to survey anonymity. NJ NG included greater proportion of Hispanics, fewer non-Hispanic whites than a national NG sample, though few differences in current data on race. Similar to national sample on heavy drinking and 12 month

Binge drinking last 6 months

7.0 4.7 adj OR 2.29 1.51, 3.48

Heavy drinking last 12 months

19.5 20.3 adj OR 1.25 0.97, 1.62

Illicit drug use last 12 monthsa

10.0 11.6 adj OR 0.91a 0.66, 1.26

Nearly 25% previously deployed to OEF/OIF. Deployed 85.5% males, 14.5% females; non-deployed 89.0% males and 11.0% females. Males and females included in the analyses

93








drug use. Current sample 50% of NJ NG.Effect estimate adj for demographics, income, previous service in other conflicts.Overall risk of bias: low

Fear 2010 (3)

Cohort study questionnaire; 2007-09. Multiple phase study -2004-06 sample was reassessed and 2 new samples assessed

Randomly sampled UK armed forces (Army, Navy, Air Force), regulars (n=8278) and reservists (n=1712: included follow up of 2003 Iraq cohort (n=4203) (90), and two randomly sampled groups: deployment to Afghanistan only (n=1123) and Deployed to Iraq and Afghanistan (n=1389). Not deployed to Iraq or Afghanistan (n=3255).

10-item AUDIT. Score ≥16 defined hazardous use harmful to health- termed alcohol misuse

Alcohol Misuse – Regulars vs Non deployed

Iraq or Afghanistan

15.7 10.9 adj ORa 1.22 1.02, 1.46 Participation rate: 56% of eligible sampleNon response bias assessed: Mental health at stage 1 not associated with participation Sample and response weights applied in analysesOR adj for age, sex, marital, education, rank, serving status and serviceOverall risk of bias: low

Iraq only 15.3 10.9 adj OR 1.21 0.99, 1.46

Afghanistan only 17.8 10.9 adj OR 1.20 0.92, 1.57

Both Iraq and Afghanistan

15.1 10.9 adj OR 1.30 1.01, 1.67

Regulars: Combat vs combat service support

22.5 14.2 Adj OR 1.15 0.93, 1.42

Combat support vs combat service support

10.8 14.2 Adj OR 0.68 0.50, 0.93

Iraq or Afghanistan 9.5 6.8 Adj ORa 1.38 0.89, 2.13

Deployed to Iraq 90.6% males, 9.4% females; Afghanistan only 94.5% males, 5.5% females; deployed to Iraq and Afghanistan 94.3% males, 5.7% females (n=1389); not deployed to Iraq or Afghanistan 86.8% males, 13.2% females (n=3255).

Shen 2012 (78)

Database analysis on several

678 382 unique active duty personnel

ICD-9 diagnosis of any substance use/ dependence

Any substance use/ dependence

Army 14.8 6.0 Adj OR 4.05 3.82, 4.30 Sample 25% and representative of US Armed Forces active duty

Marines 9.3 5.0 Adj OR 4.36 3.82, 4.97Navy 8.6 8.0 Adj OR 1.77 1.45, 2.16

94








combined sources from US Defense Manpower Data Center and TRICARE, to obtain active duty personnel, demographic service, mental and related health information

serving b/n 2001 and 2006, approx 49% Army, 14% Marine, 20% Navy, 17% Air Force. Four groups: Not deployed under OEF/OIF; Deployed- Iraq or Afghanistan; Other known locations under OEF/OIF, e.g. Kuwait, Qatar, Turkey; Classified/ unknown locations

disorder between 2001 and 2006; according to DSM-IV criteria. Also considered 3 deployment lengths (data not shown)

Deployed Iraq or Afghanistan vs Not deployed

population, Captured diagnoses from in and outpatient settings and civilian and military providers.Undertook sensitivity analyses. OR adjusted for demographic (gender, race/ethnicity, marital age) and service characteristicsOverall risk of bias: low

Air Force 7.1 5.9 Adj OR 1.76 1.56, 1.99

OEF-OIF deployed females - Army 11% Marines 3%, Navy 13%, Air Force 15% and similar to Not deployed.

Vanderploeg 2012

Cross sectional anonymous

Current active members of the Florida National

AUDIT identifying excessive drinking behaviours. Cutoff

Excessive drinking

38.4 29.8 adj OR (males and

0.75a 0.57, 1.00 Participation rate: 41.3% (9700 eligible)

95








(79) online survey; 2009-10

Guard who were deployed to OEF/OIF (n=1443) and not deployed (n=1655)

ref to Hoge (74) which measured alcohol misuse using a 2-item screening instrument (104)

females) Effect estimate adj for other covariates, demographic, pre-deployment factors

Non response bias not assessed due to survey anonymity, No information on Florida NG cohort available Overall risk of bias: high

Deployed 87.4% males, 12.6% females, non-deployed 79.2% males, 20.8% females

Trautmann 2014 (98)

Cross sectional clinical- epidemiological study including face-to-face diagnostic interviews; 2010-2011

German soldiers examined about 12 months after deployment to Afghanistan in 2009/2010 (n=1483) and randomly selected never deployed soldiers stratified by age, sex and unit grid (n=889)

Munich-CIDI using DSM-IV criteria to assess AUD, and to derive binge drinking (≥7 drinks on 1 occasion) and heavy drinking (≥24g for men or ≥16g for women of ethanol /day)

Any AUD last 12 months

3.6 2.2 adj OR (males and females)

1.9a

1.0

1.1

0.6a

0.99, 3.5

(0.7-1.3)

(0.8-1.6)

(0.2-2.0)

Participation rate: 92.8% (1599 eligible deployed Afghanistan) vs 95.4% (932 eligible never deployed)Effect estimate adj for demographics, economic situation, service length, unit, rank.Eligible and non-eligible soldiers similar. Never deployed and deployed comparableOverall risk of bias: low

Binge drinking 36.2 38.1Heavy drinking 13.9 13.9SUD 1.0 1.7Deployed and never deployed both 95.0% males

AUDIT, World Health Organization Alcohol use disorder identification test (99); CAGE,CAGE Questionnaire (100); CIDI, World Health Organization Composite International Diagnostic Interview (38); NG, National Guard ; Non-deployed /non-Afghanistan/Iraq, a military comparison group who were not deployed to Afghanistan/Iraq War during the period of operations. OR, Odds Ratio

a OR data used in the meta-analyses

96

4.6.2 Key findings

Nine studies in Gulf War veterans and nine studies in Afghanistan/Iraq War veterans met the

inclusion criteria. Pooled analysis based on random-effects model indicated that Gulf War

veterans and Afghanistan/Iraq War veterans were at higher alcohol use disorder risk than military

personnel not deployed to these conflicts respectively, with the summary ORs being very similar

for the two groups. The summary estimate of the likelihood of alcohol use disorders was slightly

higher, but not statistically significant, in reservists compared with regular personnel deployed to

Afghanistan/Iraq War. Veterans of the Afghanistan/Iraq War were at increased risk of substance

use disorders, but it was difficult to draw definitive conclusions regarding substance use disorders

in Gulf War veterans since only three studies were available reporting this outcome and the

elevated meta-analytic estimate had very wide confidence intervals. Our meta-analysis also

suggested that Gulf War veterans were at a significantly increased risk for any substance use

disorder compared with military personnel who were not deployed to the Gulf War. The results

from alcohol and any substance use disorder outcomes were robust to the impact of risk of bias,

publication bias and our sensitivity analyses.

97

4.7 Generalised anxiety disorder in Gulf War and Afghanistan/Iraq War veterans compared to non-deployed military personnel

4.7.1 Results

Of the 25 primary Gulf War veteran health studies identified, five studies were eligible to be

included in the systematic review and meta-analysis in relation to GAD. Of the 24 primary

Afghanistan/Iraq War veteran health studies identified, three studies reported on GAD and were

included in the meta-analysis. The characteristics of these studies are reported in Table 10 and

Table 11.

Across the five included Gulf War studies, sample sizes ranged from 204 to 1896 for Gulf War

veterans and 48 to 1799 for the non-deployed personnel; and across the three included

Afghanistan/Iraq War veteran studies sample sizes ranged from 1443 to 5325 for Afghanistan/Iraq

War veterans and from 1655 to 4886 for the non-deployed personnel. The percentage of female

veterans in these studies ranged from 1% to 22%.

All except one of the studies was based on US veteran cohorts, the other study population was

Australian Gulf War veterans. These studies included personnel from all services (Army, Navy,

Marines, Air Force, National Guard). The military comparison groups in all the studies were

described and defined as non-deployed, i.e. not deployed to the Gulf War or Afghanistan/Iraq War

during the period of operations, rather than other conflict personnel. Some studies attempted to

oversample certain groups such as women and reservists to determine whether these groups had

different rates of GAD (17). Most studies did not endeavour to sample specific categories of

military personnel in order to mirror deployment proportions, though samples were generally

representative of their populations.

Of the Gulf War studies, four used structured diagnostic interviews (CIDI or SCID) and one used a

screening tool (PRIME-MD). For the outcome of GAD, two provided data for adjusted OR in the

published article. The other three studies provided usable data in the published article for

calculation of an unadjusted OR. Of the Afghanistan/Iraq War veteran studies, all three studies

used screening tools (PHQ or 7Q-GAD scale). Two provided adjusted ORs, and the third provided

an adjusted prevalence. The authors of this study had been contacted and had provided on

request more precise estimates of standard errors of prevalence that enabled calculation of ORs.

98

Gulf War veteran studies reporting GAD

The overall OR using the random effects model for the five included studies was 3.04 (95% CI:

1.95, 4.75) which indicated a significantly higher risk of GAD in Gulf War veterans compared to

non-deployed military personnel. Overall heterogeneity for all studies represented by I2 was low to

moderate at 35% (Figure 26). Sensitivity analyses indicated that the overall OR did not vary much

after excluding any individual study of the five included studies. Black et al. (17) reported ORs

separately for reservists and regular military personnel. These two subpopulations were also

entered separately into the meta-analyses. Excluding the reservists’ subgroup caused the OR to

decrease the most to 2.40 (95% CI: 1.65, 3.49).

Figure 26 Random-effects meta-analysis illustrating log-transformed odds ratios of generalised anxiety disorder in Gulf War veterans and non-deployed military personnel

Stratification by case definition indicated that the diagnostic interview subgroup (OR = 2.48, 95%:

1.49, 4.10) and screening tool subgroup (OR = 3.40, 95%: 1.59, 7.27), with only one study in it but

two subpopulations, had broadly similar ORs and confidence intervals. Heterogeneity was 0% in

the diagnostic interview subgroup but high and statistically significant in the screening tool

99

subgroup (I2=73%, p=0.05); the screening tool subgroup contributed more weight in calculating the

overall OR (58.68%) (Figure 27).

Figure 27 Random-effects meta-analysis of generalised anxiety disorder in Gulf War veterans and non-deployed military personnel, subgrouped by case definition

The studies were further stratified based on risk of bias, and the OR in both subgroups were

comparatively similar (low risk of bias subgroup OR = 3.34, 95% CI: 1.86, 5.99; high risk of bias

subgroup OR = 2.89, 95% CI: 0.77, 10.94). Heterogeneity was 47% in the low risk subgroup and

33% in the high risk subgroup, but both figures were not at the level of significance. The low risk

subgroup contributed substantially more weight to the overall OR (Figure 28).

Three of the five studies received a high overall risk of bias. Common factors contributing to this

assessment were poorer sample designs (i.e. convenience samples, non-random sample), lack of

adjustment for possible confounding factors, high non-response rates and lack of calculation of

ORs. All of the studies that did not report adjusted ORs were assessed as having an overall high

risk of bias.

100

Figure 28 Random-effects meta-analysis of generalised anxiety disorder in Gulf War veterans and non-deployed military personnel, subgrouped by risk of bias

Afghanistan/Iraq War veteran studies reporting GAD

The Hoge et al. (74) study reported ORs for three distinct subpopulations based on theatre of

operation (OEF, Afghanistan or OIF, Iraq) and service branch (Army or Marines). Thus these

subpopulations were combined using Stata (version 11) and entered separately into the meta-

analysis, in order to avoid triple counting the non-deployed group. It also reported ORs using

either a strict or broad definition of GAD based on the Patient Health Questionnaire (PHQ)

screening tool, where the strict case definition required reporting of functional impairment to make

a positive diagnosis of GAD, and the broad case definition focussed only on reported symptoms for

a positive diagnosis. The strict PHQ definition of GAD was used in order to limit heterogeneity in

the meta-analysis, as it was more similar to the case definitions used by Vanderploeg et al. (79)

and Bray et al. (91).

The overall OR using the random effects model for the three included studies was 1.20 (95% CI:

1.00, 1.44) which indicated a statistically significantly higher risk of GAD in Afghanistan/Iraq War

101

veterans compared to non-deployed military personnel. Heterogeneity was detected at 0% (Figure

29).

Figure 29 Random-effects meta-analysis illustrating log-transformed odds ratios of generalised anxiety disorder in Afghanistan/Iraq War veterans and non-deployed military personnel

Subgroup analyses by risk of bias, case definition or any other factor could not be done due to the

low number of studies. Both Hoge et al. (74) and Bray et al. (91) were assessed as low risk of bias

whereas Vanderploeg et al. (79) was assessed as high risk of bias due to a low study response

rate and inability to assess non-response bias. However, sensitivity analyses indicated that the

overall OR did change and become non-significant after excluding either the Bray et al. (91) study

or Hoge et al. (74) study. The Bray (2006) study was completed as part of a US Department of

Defense survey solely on reservists (from all service branches) and National Guard personnel. For

this reason the study was removed to ascertain the effect on the meta-analysis: the OR decreased

to 1.14 (0.94, 1.40) and became non-significant (Figure 30).

102

Odds Ratio

Figure 30 Random-effects meta-analysis of GAD in Afghanistan/Iraq War veterans compared to non-deployed military personnel, sensitivity analysis excluding Bray (2006)

Comparison of summary odds ratio of generalised anxiety disorder in Gulf War veterans versus Afghanistan/Iraq War veterans

Furthermore, the summary OR of GAD in Gulf War veteran studies (OR 3.04, (95% CI 1.95, 4.75)

was statistically significantly higher than the summary OR (OR 1.20, 95% CI 1.00, 1.44) for the

Afghanistan/Iraq War veteran studies, as their respective confidence intervals did not overlap.

103

Table 10 Characteristics of eligible studies comparing prevalence of generalised anxiety disorder (GAD) in Gulf War veterans and non-deployed military personnel

First author


Sample GAD case definition and measure


(%)

Comp group

prevalence (%)

Odds Ratio (95% CI)

Participation rates; Assessment of overall risk of bias

Black 2004 (17)

Cross-sectional, structured telephone interview; 1995 to 1996

Random sample GWV selected from Iowa US; regular military (Reg) (n = 985), GW National Guard (NG)/Reserve (Res) (n = 911), non-GW regular military (n = 968), and non-GW NG/Res (n = 831)

PRIME-MD, based on the DSM-IV; GAD required 3 or more symptoms of anxiety for past year and anxiety/worry more days than not during past 12 months

12 month GAD (Reg)*

3.9 1.9 2.3 (1.3-4.0) Study participation rates: 91% (76% of eligible)Non-response bias assessed in study: noOverall risk of bias: low

12 month GAD (NG/Res)*

4.5 1.0 5.0 (2.9-8.8)

12 month GAD (total)

4.0 1.8 2.5 (1.5-4.1)

Prevalences weighted to account for complex study design; ORs adjusted for age, sex, race, rank, branch of service, military status, and pre-GW mental health conditionsNumber of females in sample not reported

Wolfe 1999 (6)

Cross-sectional; in-person structured clinical interview by trained clinicians; 1994 to 1996

Stratified, random sample two cohorts US GWV from Fort Devens, New England (FD, n = 148) and New Orleans, (NO, n = 56), comparison group of air ambulance unit deployed to Germany during GW (G, n = 48)

SCID non-patient edition to assess current (within 1 month) GAD disorder

1 month GAD (FD)

0.8 0.0 Study participation rates: 62% (FD; 353 eligible); 38% (NO; 194 eligible); 85% (G; eligible numbers not reported)Psychological interview participation rates: 42% (FD), 30% (NO), 51% (G)Non-response bias assessed in study: yes, for demographics, health outcomesSignificant differences between respondents and non-respondents: yes, on demographics and health outcomesOverall risk of bias: high

1 month GAD (NO)

0.0 0.0

1 month GAD (total)*

0.8 0.0 0.71 (0.03-17.82)a

Prevalences adjusted for stratification variables of gender and health symptomsFemales made up 12.0% of total sample

Toomey 2007 (67)

Cross-sectional, in-person computerised diagnostic interview; 1998 to 2001,

Stratified, random subsample of previous study by Kang (1995). US GWV (n = 1061) and non-deployed (n = 1128)

CIDI using DSM-IV criteria to assess 12-month GW-era onset (Jan 1991-July 1993) GAD; Beck Anxiety Inventory

GW-era onset GAD

0.9 0.0 22.54 (1.32-385.1)a

Psychological interview completion rates: 53% GWV (1996 eligible) 39% non-GWV (2883 eligible)Non-response bias assessed in study: yes, for demographics, health outcomesSignificant differences between respondents and non-respondents: yes,

Females made up 22% of the total sample

104

First author




(%)

Comp group

prevalence (%)

Odds Ratio (95% CI)


10 years after the war

assessed past week anxiety symptoms-total score indicating minimal (0-7), mild (8-15), moderate (16-25), severe (26-63) anxiety

on demographics; not on health outcomesOverall risk of bias: high

Ikin 2004 (1)

Cross-sectional, in-person structured diagnostic interview by trained psychologists; 2000 to 2002, 10 years after the war

All Australian GWV (n = 1381) and random sample of Navy, Army and Air Force non-deployed active duty personnel (n = 1377) matched by age, gender and service type

CIDI using DSM-IV criteria to assess post-Gulf War GAD

First present post-GW GAD*

0.7 0.2 2.9 (0.7-16.4) Participation rate: 81% GVW (1808 eligible); 57% non-GWV (2796 eligible)Psychological interview completion rates: 78% GWV; 51% non-deployedNon-response bias assessed in study: yes, for demographics, health outcomesSignificant differences between respondents and non-respondents: yes, on demographics; not on health outcomesOverall risk of bias: low

Pre- and post-GW GAD in previous 12 months

0.4 0.1 2.6 (0.5-27.0)

OR were adjusted for service type, rank, age, education and marital status or where numbers were small for service type, rank and ageFemales made up 2.4% of the total sample. Analyses were restricted to males only

Fiedler 2006 (66)

Cross-sectional, telephone structured diagnostic interview by trained interviewers; 2000 to 2001

Random sample (n = 967) of all US GWV and non-deployed personnel (n = 784)

CIDI-Short Form (SF) using DSM-IV criteria to assess 12 month GAD

12 month GAD (total)*

6.0 2.7 2.32 (1.37-4.06)a Participation rates: 59% GVW (1651 eligible); 51% non-GWV (1552 eligible)Psychological interview completion rates: 55% GWV; 43% non-deployedNon-response bias assessed in study: yes, for demographicsSignificant differences between respondents and non-respondents: yesOverall risk of bias: high

12 month GAD (males)

5.8 2.2

12 month GAD (females)

8.0 6.5

Females made up 9.6% of total sample

Gulf War, Gulf War veterans and non-deployed comparison group/s abbreviated as GW, GWV and non-GWV for brevity; a = Unadjusted OR (Calculated through Stata 11 and RevMan 5.3 using reported prevalences and sample sizes for deployed and non-deployed personnel); * Odds ratios that were used in the meta-analyses; OR = Odds Ratio; NG= National Guard; Res= Reserve; non-deployed = a military comparison group who were not deployed to the Gulf War during the period of operations; CIDI = World Health Organization Composite International Diagnostic Interview (38); SCID = Structured Clinical Interview for DSM Disorders; PRIME-MD PHQ = Primary Care Evaluation of Mental Disorders Patient Health Questionnaire based on DSM-III-R criteria (105)

105

Table 11 Characteristics of eligible studies comparing prevalence of generalised anxiety disorder (GAD) in Afghanistan/Iraq War veterans and non-deployed military personnel

First author




(%)


Odds Ratio (95% CI)


Vander-ploeg 2012 (79)

Cross-sectional, anonymous online survey; 2009 to 2010

Sample from all active members of the Florida NG (n = 3098), comprising deployed group (n = 1443) and non-deployed group (n = 1655)

7-question Generalized Anxiety Disorder scale; reported nervousness or worry more than half the time, 3 of 6 other anxiety symptoms more than half the time, and impairment in functioning at the “very difficult” level.

Current GAD 4.2 1.5 0.70 (0.23-2.15) Study participation rates: 41.3% overall (10,400 eligible)Non-response bias assessed in study: no due to survey anonymityOverall risk of bias: high

OR adjusted for all other covariates, and demographic (sex, race, education level, marital status) and pre-deployment (prior psychological trauma or probable TBI) factorsFemales made up 17.0% of the total sample

Hoge 2004 (74)

Cross-sectional, in-person questionnaire; 2003

Samples from Army combat infantry brigade pre deployment to Iraq (n = 2530); an infantry brigade of same division post deployment to Afghanistan (n = 1962); an Army infantry brigade of post Iraq deployment (n = 894); and Marine Corp units post Iraq deployment (n = 815)

Patient Health Questionnaire (PHQ), modified slightly; two case definitions- broad screening definition not including criteria for functional impairment or for severity, strict screening definition requiring self-report of substantial functional impairment or a large number of symptoms

Current GAD (broad)

Army, Afghan.

17.2 15.5 1.13 (0.96-1.33) Non-response bias assessed in study: noStudy participation rates: 98% for the four samples combinedQuestionnaire completion rate: 95% for the anxiety and depression measuresThe demographic characteristics of the sample closely mirrored that of the populationOverall risk of bias: low

Current GAD (strict)

7.4 6.4 1.17 (0.92-1.48)

Current GAD (broad)

Army, Iraq

17.5 15.5 1.16 (0.94-1.43)


7.9 6.4 1.25 (0.92-1.68)

Current GAD (broad)

Marine Corp, Iraq

15.7 15.5 1.02 (0.81-1.27)


6.6 6.4 1.03 (0.74-1.43)

Current GAD (strict)*

Deployments combined 1.16 (0.94-1.43)

OR adjusted for differences in demographic characteristics before and after deployment (age, sex, race, education level, rank, marital status)Females made up 1.0% of the total sample

106

First author




(%)


Odds Ratio (95% CI)


Bray 2006 (91)

Cross-sectional, self-report questionnaire survey; 2006 (9th data point in series since 1980)

Sample of all US reserve and NG military personnel (excluded recruits, academy students, AWOL or had permanent change of station) comprising army, navy, marine and air force reserve and coast guard. Served in OEF/OIF (n = 5325) and those non-deployed (n = 4886)

PHQ; if bothered by feelings of anxiousness for several days in the past month (30 days) and had at least three other symptoms for more than half the days, they were scored as needing further anxiety evaluation

1 month GAD 12.76 (SE 1.36) 9.13 (SE 0.76) 1.41 (0.97-2.01)a Overall response rate: 55.3%Non-response bias assessed in study: yes, a non-response adjustment was made to help compensate for the potential bias of nonsurveyed personsOverall risk of bias: low

Prevalences adjusted corrected for differences in the demographic distributions between the two groups. The main effect of reserve component, gender, age group, enlister/officer indicator, married/other, education and race/ethnicity were used in this standardisation processFemales made up 21.2% of the total sample

a = Unadjusted OR (Calculated through Stata 11 and RevMan 5.3 using reported prevalences and sample sizes for deployed and non-deployed personnel); * Odds ratios that were used in the meta-analyses; OR = Odds Ratio; NG= National Guard; OEF= Operation Enduring Freedom (Afghanistan); OIF= Operation Iraqi Freedom; non-deployed = a military comparison group who were not deployed to the Afghanistan/Iraq War during the period of operations.

107

4.7.2 Key findings

The summary OR using the random effects model for the five included studies in the meta-analysis

of GAD indicated Gulf War veterans were at three times the odds of GAD compared with non-

deployed military personnel. Overall heterogeneity for all studies represented by I2 was moderate

at 35%, but not statistically significant. This finding did not vary much after excluding individual

studies one by one in sensitivity analyses. In subanalyses the OR for GAD in Gulf War was lower,

but still increased over two-fold, in the subgroup assessed by diagnostic interview, and in subgroup

analysis when the reservist subgroup in one of the studies was excluded. The number of studies

was small however and these findings should be interpreted with caution.

The summary OR using the random effects model for the three included studies in the meta-

analysis indicated that Afghanistan/Iraq War veterans were at twenty percent increased odds of

GAD compared with non-deployed military personnel. Heterogeneity was not at a detectable level.

Further subanalyses could not be undertaken due to the small number of studies. However, when

a study that was undertaken solely on reservists and National Guard was excluded, the OR

decreased and was not statistically significant.

The difference in pooled OR between Gulf War veteran studies and Afghanistan/Iraq War veteran

studies was statistically significant, as their respective confidence intervals did not overlap.

108

5 Multisymptom illness in Gulf War, Afghanistan and Iraq War veterans compared to non-deployed military personnel


Figure 31 shows that the search yielded 2,573 records, with 2,445 records remaining after removal

of duplicates. The titles and abstracts were screened to identify studies for full- text review by the


for further review, and seven eligible articles were identified reporting multisymptom illness

according to the eligibility criteria. Figure 31 also identifies the reasons for excluding full text

articles that were assessed for eligibility for multisymptom illness.

109

2,573 Records Identified Through Database Search and Additional Searching

7 Eligible Studies Reporting Multisymptom Illness (one

study had two articles)7 Gulf War veterans

0 Afghanistan/Iraq veterans

122 Full-text Articles Excluded because:2 Subanalysis of MSI4 Deployment was not specified or non-Gulf/Afghanistan/Iraq77 Inappropriate comparison group or case definition or no measure of MSI 38 Study not original research or odds ratio not calculable 1 Study based on treatment seeking sample

130 Full-text Articles Assessed for Eligibility

2,315 Abstracts Excluded

2,445 Abstracts Assessed For Eligibility (excluding

duplicates)

Figure 31 Flowchart of the systematic review of multisymptom illness (MSI) Gulf War veterans, Afghanistan/Iraq War veterans, 1990-2014

The systematic review identified seven studies of veterans from the 1990-1991 Gulf War, five from

the US, one from the UK and another from Australia. No studies of Iraq or Afghanistan veterans

were identified. Hence the rest of this section is based on Gulf War veterans alone.

The key features of the selected studies are summarised in Table 13 and the studies are arranged

according to the year in which data were collected. All studies were cross-sectional and the

methods of data collection used were similar across studies except that some studies used postal

questionnaires while other studies complemented this through telephone interviews. The study

populations in most studies included a range of military service branches, an exception was the

study by Fukuda et al. (27) which was conducted among US Air Force personnel only, while the

study by Kelsall et al. (1) invited all Australian Gulf War veterans to participate but the Gulf War

cohort was predominantly Navy personnel. The definition of multisymptom illness used in most

studies included was very similar to the three symptom groupings developed by Fukuda et al. (27)

(also termed as the CDC definition). Only the studies by Kelsall et al. (2006) and Kang et al.

(2009) (31) used modifications of the CDC definition. Kelsall et al. (2009) (1) multisymptom illness

definition included symptoms across multiple body systems and was based on the CDC definition,

but the symptom groupings were derived from factor analysis empirically derived in Australian Gulf

War veterans and included three symptom groupings rather than the two symptom groupings

identified by Fukuda et al. (27) Kang et al. (31) multisymptom illness definition used a multi-body

system-like definition although it was less methodically described.

Three studies were assessed as having overall high risk of bias and these were the studies by

Fukuda et al. (1998), Proctor et al. (2001) and Kang et al. (2009). The rationale for this

assessment included that in the study of Fukuda et al. (27) only serving members were included,

the response rate was moderate and unadjusted ORs only were available. The Devens cohort,

reported by Proctor et al. (2001) (106) was not considered representative of the target population

and had a moderate response rate with significant differences between participants and non-

participants (107). As mentioned above, the multisymptom illness definition as reported by Kang et

al. (2009) was less methodically described than others, but sufficiently to include, and the response

rate was relatively low.

110

5.2 Multisymptom illness in Gulf War veterans compared to non-deployed military personnel

5.2.1 Results

Meta-analysis of the seven eligible studies showed that the odds of multisymptom illness were

more than two and a half times greater in Gulf War veterans compared with the non-deployed

comparison groups (OR = 2.74, 95% CI 2.15, 3.51) (Figure 32). Figure 32 also presents the study-

specific effect sizes. Between–study heterogeneity was high (I2=92%).

OR54321

Study

Kelsall 2009

Blanchard 2006

Proctor 2001

Unwin 1999 & 2002

Overall

Q=70.25, p=0.00, I2=91%

Kang 2009

Steele 2000

Fukuda 1998

OR (95% CI) % Weight

1.80 ( 1.48, 2.19) 15.69

2.16 ( 1.61, 2.90) 13.95

2.40 ( 1.10, 5.30) 6.26

2.41 ( 2.10, 2.76) 16.54

2.74 ( 2.15, 3.51) 100.00

3.05 ( 2.77, 3.36) 16.98

3.26 ( 2.48, 4.28) 14.35

4.69 ( 4.00, 5.51) 16.23

Odds ratio

Figure 32 Random-effects meta-analysis of multisymptom illness in Gulf War veterans and non-deployed military personnel

Subgroup analyses were also conducted to further explore factors that could explain heterogeneity.

Analysis by risk of bias showed that the estimated summary OR among studies with low risk of

bias was OR 2.33 (95% 1.87, 2.91; I2=77%) and the estimate summary OR from studies with high

risk of bias was greater with an OR 3.51 (95% CI 2.41-5.13; I2=91%). The summary OR of the

high risk of bias studies was estimated 52% higher than estimated by the studies with low risk of

bias, but this was not statistically significant (OR = 1.52, 95% CI 0.89, 2.61).

111

Further subgroup analysis was conducted among Fukuda et al. and the four studies that based

their definition of multisymptom illness on the three groupings of symptoms used in the CDC

definition (excluding Kelsall et al. (2009) and Kang et al. (2009)). Subgroup analysis of

multisymptom illness in these five studies found that the odds of multisymptom illness was almost

three times greater among Gulf War veterans than the comparison groups (OR = 2.93, 95% CI

2.06, 4.18; I2=91%)

Sensitivity analyses, presented in Table 12, did not reveal any marked study specific effects with

the exception of the study reported by Fukuda et.al. (1998).

Table 12 Sensitivity analyses excluding each study one by one for studies of multisymptom illness in Gulf War veterans compared to non-deployed military personnel

Excluded study Overall

Pooled ES 95% CI I 2

Fukuda 1998 2.48 2.03 – 3.03 83%

Proctor 2001 2.77 2.14 – 3.58 93%

Steele 2000 2.66 2.02 – 3.51 93%

Unwin 1999 & 2002 2.81 2.08 – 3.78 92%

Blanchard 2006 2.85 2.18 – 3.73 92%

Kelsall 2009 2.98 2.35 – 3.78 89%

Kang 2009 2.68 1.91 – 3.75 93%

ES= effect size

Presented in Figure 33 is the funnel plot. A visual inspection of the funnel plot shows that six of the

seven studies were symmetrically distributed across the top of the funnel (with one smaller study

within the funnel at the base). The horizontal scatter around the summary fixed estimate is

suggestive of study heterogeneity. (Note: FE MA, Fixed effects meta-analysis)

112

Figure 33 Funnel plot for the random-effects meta-analysis of multisymptom illness Gulf War veterans and non-deployed military personnel

113

Table 13 Characteristics of eligible studies comparing prevalence of multisymptom illness in Gulf War veterans and non-deployed military personnel

First Author


Sample Multisymptom illness (MSI)case definition*

GWV prevalence

(%)


(%)

ES(Adj. OR)

95% CI Comments and Assessment of overall risk of bias

Fukuda, 1998(27)

Cross sectional study with self-administered questionnaires, 1995

US Air Force personnel stationed at 4 Air Force bases.N=1,163 GWVN=2,560 non-GWV

CDC definition: Presence, for 6 months or more, of at least one symptom from two or more symptom groupings namely (i)fatigue; (ii) mood/cognition (i.e. feeling depressed, difficulty remembering or concentrating, feeling moody, feeling anxious, trouble finding right words or difficulty sleeping); and (iii) musculoskeletal (i.e. joint pain/stiffness or muscle pain). The symptom groupings mood/cognition and musculoskeletal were derived through exploratory principal components analysis in this study group

45 15 Mild-Moderate: 4.08Severe: 16.18

No adjusted combined estimate

3.39-4.93

8.99-29.14

Participation rates: Participation in the study was 61% (3723/6151) and it is not presented separately for GWV and non-GWV)Non-response bias was assessed and concluded that demographic characteristics of participants were similar to those of their respective units.Factors adjusted for in estimation of OR were not listedOverall risk of bias: High

Proctor, 2001(106)

Cross sectional study with self-administered questionnaires, 1994-1996.

Gulf War and German (deployed during Gulf War) veterans from Ft Devens (Massachusetts, US).N=180 GWVN=46 non-GWV

CDC-derived definition: Presence, for 6 months or more, of at least one symptom from two or more symptom groupings namely (i) fatigue (i.e. fatigue or easily tired); (ii) mood/cognition (i.e. frequent periods of feeling depressed, forgetfulness, difficulty concentrating, crying easily, excessive anger or irritability, frequent periods of anxiety and nervousness, inability to fall asleep, restless or unsatisfying sleep or awake earlier than desired); and (iii) musculoskeletal (i.e. neck aches/ stiffness or joint pains). The symptoms also needed to have begun during or after the Gulf War

65.3 32.6 2.4 1.1-5.3 Participation rates: 62% in GWV & 51% in non-GWV.Non-response bias was assessed only among GWV and participants differed from non-participants with respect to sex, race/ethnicity, age, education and symptomatology as reported in the Phse-1 study. Other factors were similar (i.e. employment status, marital status, alcohol/drug use, or service status).(107)ORs adjusted for participation bias, age and psychiatric casenessOverall risk of bias: High

Steele, 2000 (29)

Cross-sectional

US GWV and non-GWV residing in

CDC-derived definition: Presence of at least one symptom from two or more

47.2 19.8 3.26 2.48-4.28 Participation rates: 93% GWV & 88% in non-GWV.

114

First Author



GWV prevalence

(%)


(%)

ES(Adj. OR)


telephone interview; 1998

Kansas and non-deployed comparison groupN = 1,548 GWVN = 482 non-GWV

symptom groupings namely (i) fatigue; (ii) mood/cognition (i.e. feeling down/depressed, memory problems, difficulty concentrating, trouble finding words, problems falling or staying asleep); and (iii) musculoskeletal (i.e. joint or muscle pain).

Participation was significantly higher among females than malesOR was adjusted for age, gender, rank, service branch, component, income and education level.Overall risk of bias: Low

Unwin, 1999 & 2002(9, 88)

Cross-sectional postal survey, 1997

UK male and female veterans of the 1991 Gulf War; 1992-1997 Bosnia war and non-deployed veterans (also termed Gulf-Era veterans).N= 3,510 GWVN= 2,040 Bosnia veteransN= 2,600 Gulf era veterans

CDC-derived definition: Presence, for a month or more, of at least one symptom from two or more symptom groupings namely (i) fatigue; (ii) mood/cognition (i.e. depression, poor concentration/memory, moodiness, anxiety, word-finding difficulties or sleep difficulties); and (iii) musculoskeletal (i.e. joint or muscle pain, joint stiffness)

62.0 Bosnia: 36.6Gulf-Era: 36.3

Bosnia: 2.42Gulf-Era: 2.41

2.06-2.85 †2.10-2.76 †

Participation rates: 70% in GWV, 62% in Bosnia veterans and 63% in Gulf-Era group.Non-response bias was assessed and sex distribution and number of medical discharges were similar for participants and non-participants. Participants were more likely to be older or still servingOR was adjusted for age, marital status, rank, education, employment, discharge status, smoking status, alcohol consumption, general health questionnaire scoresOverall risk of bias: Low

Kelsall, 2009 (20)

Cross-sectional postal survey, 2000-2002

Australian male veterans of the 1991 Gulf War and non-Gulf War deployed veterans .N= 1,381 GWVN= 1,377 non-GWV

CDC-modified definition: Presence, for a month or more, of at least one symptom rated as moderate/severe from three or more symptom groupings namely (i) fatigue; (ii) psycho-physiological distress (e.g. vomiting/nausea, stomach cramps, diarrhoea, wheezing, indigestion, persistent cough, fainting, dizziness, difficulty speaking); (iii) cognitive distress (e.g. loss of concentration,

25.6 16.0 1.80 1.48-2.19 Participation rates: 81% in GWV and 57% in non-GWV.Non-response bias was assessed and participants were more likely to be older and of higher ranks than non-participants. Participation of Air Force personnel was higher among non-GWV than GWV.ORs were adjusted for age, service branch, rank, marital

115

First Author



GWV prevalence

(%)


(%)

ES(Adj. OR)


feeling distant, sleeping difficulties, distressing dreams, irritability/outbursts of anger); and (iv) arthro-neuromuscular distress (e.g. joint stiffness, general muscle aches, low back pain, joint pain without swelling or redness). The symptom groupings psycho-physiological distress, cognitive distress and arthro-neuromuscular distress were derived through exploratory factor analysis of symptoms reported by Australian GWV (108)

status and highest level of educationOverall risk of bias: Low

Blanchard, 2006 (21)

Cross-sectional face-to-face interviews, 2001

US Gulf War veterans and non-deployed veterans.Ν=1,035 GWVΝ= 1,116 non-GWV

CDC-derived definition: Presence, for 6 months or more, of at least one symptom from two or more symptom groupings namely (i) general fatigue; (ii) mood/cognition (i.e. feeling depressed, feeling irritable, difficulty thinking/concentrating, feeling worried/tense/anxious, problems finding words, problems getting to sleep); and (iii) musculoskeletal (i.e. joint pain, muscle aches/pain)

28.9 15.8 2.16 1.61-2.90 Participation rates: 53% in GWV & 39% in non-GWVNon-response bias was assessed and participants were more likely to be female, older, white, in the reserve and using results of an earlier study were more likely to have reported more symptoms and illnesses than non-participantsOR was adjusted for age, gender, race, education, duty type, service branch, rank, income, combat exposure, Khamisiyah exposure, psychiatric conditions with onset prior January 1 1991 and self-reported doctor diagnosed medical conditionsOverall risk of bias: Low

Kang, 2009 (31)

Cross sectional postal and telephone

US GWV and non-deployed Gulf Era personnel. N = 6,111 GWV

Presence of several different symptoms together that persisted for 6 months or more and could not be adequately explained through medical or

36.5 11.7 3.05 2.77-3.36 Participation rates: 40% GWV and 27% non-GWV.Non-response bias was assessed and non-respondents were more

116

First Author



GWV prevalence

(%)


(%)

ES(Adj. OR)


interviews, 2003-2005

N = 3,859 non-GWV psychiatric diagnoses. The list of symptoms might include things like fatigue, muscle/joint pain, headaches, memory problems, digestive problems

likely to be younger, single, non-white or enlisted rank in 1991 than participantsDefinition of multisymptom illness adopted in the study was similar to CDC but not clearly definedOR was adjusted for age, gender, race, body mass index, cigarette smoking, rank, service branch, unit component (active duty, National Guard or reserve)Overall risk of bias: High

Abbreviations: GWV=Gulf War veterans; non-GWV=non-Gulf War veterans; ES=effect size; OR=odds ratio; CI=confidence interval

* The CDC-derived definitions are multisymptom illness definitions which were developed on the basis of the multisymptom illness definition developed by Fukuda et al. (1998)(27), which was also referred to as the CDC definition. Variations in symptoms listed under each of the three symptom groupings depended on the list of symptoms used in each of the studies.

† The odds ratios were combined for males and females

117

5.2.2 Key findings

Seven eligible articles were identified reporting multisymptom illness according to the eligibility

criteria which included studies that used the CDC definition for multisymptom illness. All of these

studies were in Gulf War veteran populations, there were no eligible studies identified in

Afghanistan or Iraq War veteran populations. Meta-analysis of the seven eligible studies showed

that the odds of multisymptom illness were more than two and a half times greater in Gulf War

veterans compared with non-deployed comparison groups. There was a high amount of statistical

heterogeneity. Subanalysis conducted based on five studies that used the CDC definition of three

groupings of symptoms to define a multisymptom illness case showed that the OR increased

slightly to around three fold in Gulf War veterans compared with non-deployed military comparison

group. The odds of multisymptom illness and the heterogeneity in studies decreased in the

analysis involving just the four studies assessed as overall low risk of bias.

118

6 Chronic fatigue syndrome in Gulf War, Afghanistan and Iraq War veterans compared to non-deployed military personnel


Figure 34 shows that the search yielded 1,721 records, with 1,332 records remaining after removal

of duplicates. The titles and abstracts were screened to identify studies for full- text review by the


for further review, 11 eligible articles were identified reporting CFS according to eligibility criteria.

The reasons for excluding full text articles assessed for eligibility for CFS are also identified.

119

1721 Records Identified Through Database Search

405 Duplicates Removed

1332 Records After Duplicates Removed

1332 abstracts assessed for eligibility

1261 abstracts excluded

71 full-text articles assessed for eligibility

60 full-text articles excluded due to:

3 articles – non-specified deployment or non-Gulf/ Afghanistan/Iraq War deployment

28 articles – inappropriate or no comparison group or case definition of CFS

15 articles – fatigue outcome but no assessment of CFS

13 articles – not original research or odds ratio not calculable

1 article - treatment seeking sample

11 Eligible Articles Reporting CFS 11 in Gulf War veterans

0 in Afghanistan/Iraq War veterans

7 studies included in quantitative synthesis reporting CFS in Gulf

War veterans4 eligible articles excluded due to

overlap in study populations

16 Records Identified through Other Sources, e.g. reference lists, grey

literature

Figure 34 PRISMA flow diagram for chronic fatigue syndrome (CFS) in Gulf War, Afghanistan, Iraq War veterans

120

6.2 CFS in Gulf War veterans compared to non-deployed military personnel

6.2.1 Results

Seven studies met the eligibility criteria (19, 29, 31, 83, 106, 109, 110). The sample of veterans in

Kang 2003 and Kang 2009 overlapped so Kang 2009 (31) was excluded from the meta-analysis.

Proctor 2001 (106) reported prevalence data only and the prevalence was zero in the non-

deployed group, so an unadjusted OR was calculated by adding 0.5 to all cells.

Based on a random-effects meta-analysis, there was an increased odds of CFS in deployed

compared with non-deployed veterans (OR 7.62, 95% CI 3.91 to 14.85) (Figure 35). There was a

moderate amount of statistical heterogeneity (I2 = 52%).

Figure 35 Random-effects meta-analysis illustrating log-transformed odds ratios of chronic fatigue syndrome in Gulf War veterans and non-deployed military personnel

In a sensitivity analysis excluding one study which was rated at high risk of bias and which

reported an unadjusted OR (Proctor 2001) (106), the meta-analytic effect increased to OR 8.21

(95% CI 3.99 to 16.89), but statistical heterogeneity remained high (I2 = 61%). In sensitivity

121

analyses excluding each study one by one, all meta-analytic ORs remained the same magnitude,

except when Eisen 2005 (109) was removed (Table 1). There were not enough studies to perform

subgroup analyses or to assess for small study effects.

Table 14 Sensitivity analyses excluding each study one by one for studies of CFS in Gulf War veterans compared to non-deployed military personnel


Eisen 2005 4.94 4.05 6.02 1.67 0.80 0

Ismail 2008 7.84 3.35 18.33 9.93 0.04 60

Kang 2003 9.97 4.49 22.12 5.67 0.23 29

Kelsall 2006 8.15 3.78 17.59 10.45 0.03 62

Proctor 2001 8.21 3.99 16.89 10.17 0.04 61

Steele 2000 7.73 3.34 17.91 9.81 0.04 59

In the Kang 2009 study (31) which was excluded from the meta-analysis, the authors reported

prevalence data and adjusted risk ratios (RR), so we calculated unadjusted ORs based on the

prevalence data. There was an increased odds of CFS in deployed compared with non-deployed

veterans (OR 2.93, 95% CI 2.4 to 3.58; note that the adjusted RR in the paper was RR 2.38, 95%

CI 1.97 to 2.87).

6.2.2 Key findings

Seven studies met the eligibility criteria for the systematic review and six studies for inclusion in the

meta-analysis of CFS in Gulf War veterans. The number of cases of CFS in some study groups,

and non-deployed comparison groups in particular was small or none. Based on a random-effects

meta-analysis, there was an increased odds of CFS in Gulf War veterans compared with non-

deployed military personnel of over seven-fold. There was a moderate amount of statistical

heterogeneity. In sensitivity analyses, excluding each study one by one, all meta-analytic ORs

remained the same magnitude, except when Eisen 2005 (109) was removed and the OR

decreased to around four-fold of CFS in Gulf War veterans compared with non-deployed military

personnel. There were no reported studies of CFS in Afghanistan/Iraq War veterans.

122

Table 15 Characteristics of eligible studies comparing prevalence of chronic fatigue syndrome (CFS) and CFS-like illness in Gulf War veterans and non-deployed military personnel

First Author


Sample CFS definition


(%)


(%)



Steele (2000) (29)


Kansas residents who had served active military duty any period between August 1990 and July 1991 and now separated or reserve Stratified by gender and reservist status

Cases defined on basis of self-reported symptoms, fatigue characteristics and medical diagnoses, according to 1994 definition. Also self-reported CFS diagnosed by a physician

Self-reported CFS diagnosed or treated by a physician

9.0 1.0 OR 8.7 3.53, 21.46Participation rates: 93% GWV; 73% non-GWV, 91% of males, 95% of females completed the interviews of all GWV and non-GWVFor self-reported CFS diagnosed or treated by a physician, OR adjusted for sex, age, income, education level. For CFS-like illness, OR also adjusted for rank, service branch and duty statusOverall risk of bias: low

CFS-like illness 7.1 0.7 OR 8.21 2.58, 26.10

Proctor (2001) (106)

One phase of a longitudinal study of the Devens Cohort; 1994-1996

Stratified random sample (high and low symptom reporters) of the original Devens Cohort and German deployed comparison group

1994 definition based on self-reported symptoms, categorised before and after exclusionary indications ruled out

CFS-like illness before exclusionary indications ruled out

7.5 0 Not estimable Participation rates: Not reportedNon-response bias not assessedOverall risk of bias: high

CFS-like illness after exclusionary indications ruled out

2.0 0 Not estimable

Kang (2003) (83)

Phase 1 of the longitudinal National Health Survey of Gulf War era veterans and

Stratified random sample of US Gulf War veterans (Females=3000, NG=4000,

CFS-like illness defined by the 1994 definition based on self-report

CFS-like illness 5.6 1.2

Unadjusted OR

5.0 4.1, 6.2 Participation rate: 70% overall (76.3% GWV vs 63.2% non-GWV) eligible in-state and contactableNon-response bias

Adjusted OR 4.8 3.9, 5.9

123

First Author




(%)


(%)



their families; 1995-1996

Res=5000) symptoms assessed for demographics; significant differences between responders and non-responders on age, race, marital status and rankOR adjusted for age, marital status, rank and unit componentOverall risk of bias: low

Eisen (2005) (109)

Phase 2 of the longitudinal National Health Survey of Gulf War era veterans and their Families; 1999-2001

All eligible Gulf War veterans and comparison group members from the 1995 sample

1994 definition of CFS and self-reported CFS

1994 defined CFS 1.6 0.1

Unadjusted OR

17.68 4.63, 67.57 Participation rates: 53.1% (1061 of the 1996 invited to participate) GWV; 39.1% non-deployed (1128 of the 2883 invited to participate)Participation bias assessed for demographics, health outcomes: significant differences between responders and non-responders found for demographics and some service characteristics. Differences also found for some symptoms, including those suggestive of CFSFor both outcomes ORs were adjusted for age, sex, race, smoking, duty type, service branch and rank (for self-reported CFS the OR was also

Adjusted OR 40.60 10.2, 161.15

Self-reported CFS

2.3 0.4 Unadjusted OR

5.61 1.71, 18.42

Adjusted OR 8.05 1.94, 33.43

124

First Author




(%)


(%)


Participation rates, Assessment of overall risk of biasadjusted for education)Overall risk of bias: low

Kang (2009) (31)

Phase 3 of the longitudinal National Health Survey of Gulf War era veterans and their Families; 2003-2005

All eligible veterans from the original study populations (Kang 2003) were invited to participate

CFS-like illness defined by the 1994 definition based on self-report symptoms

CFS-like illness


2.93 2.40, 3.58 Participation rate: 34%. Gulf War veterans (6111; 80% males) and Gulf War-era comparison group (3589; 78% males)Non-response bias assessed for demographics; significant differences between responders and non-responders on age, race, marital status and rankRisk ratio adjusted for age, gender, race, rank, unit component, branch of service, BMI and current smoking historyOverall risk of bias: low

Kelsall (2006) (19)

Cross-sectional medical interview, structured diagnostic interview administered by trained psychologists and self-report questionnaire; 2000-2002.

All Australian GWV (n = 1871) and a random sample of non-deployed era personnel (n = 2796)

1994 definition of CFS and medically unexplained chronic fatigue

CFS 0.8 0.1 Adjusted OR 5.1 1.1, 48.5 Participation rates: 80.5% GWV (n=1456); 56.8% era non-deployed (n=1588).Non-response bias assessed for demographics; significant differences for age, service branch, rank and education.For CFS, OR adjusted for age, service branch and rank. For other outcomes, OR adjusted for age, service branch,

Medically unexplained chronic fatigue

6.6 2.9 Adjusted OR 2.3 1.6, 3.4

125

First Author




(%)


(%)


Participation rates, Assessment of overall risk of biasrank, education, marital status, smoking and alcohol useOverall risk of bias: low

Idiopathic chronic fatigue

5.7 2.9 Adjusted OR 2.1 1.4, 3.2

Ismail (2008) (110)

Phase 2 of a longitudinal UK veteran study; postal survey at phase 1 (1997-1998) and medical assessment at phase 2 (1999-2000)

At phase 1, population based survey UK Armed Forces Gulf War era veterans. Random sample of Gulf War veterans, deployed controls (Bosnia) and non-deployed controls. At phase 2, random sample who screened positive for physical disability at phase 1

1994 definition of CFS

CFS 18.0 3.0 Unadjusted OR

10.6 3.4, 32.9 Participation rate: overall 29.7% at phase 2Non-response bias not assessed. Comparison between disabled-GWV and disabled non-GW personnel indicated significant differences in GWV more likely to have discharged and differences in rankEffect estimate adjusted for age, sex, rank, marital status, alcohol-related disorders and selection bias using probability weightsOverall risk of bias: low

CFS Adjusted OR 7.8 2.5, 24.5

CFS with DSM-IV depression or anxiety


7.9 1.7, 36.3

CFS with DSM-IV depression or anxiety

Adjusted OR 9.1 1.8, 47.0

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7 DiscussionThe overall pattern of findings from these systematic reviews of psychological disorders,

multisymptom illness and CFS in Gulf War veterans, Afghanistan and Iraq War veterans was that

for virtually all of the psychological disorders, the meta-analytical summary ORs were elevated in

Gulf War or Afghanistan/Iraq War veterans compared with military personnel who were not

deployed to the corresponding conflict zone. The summary ORs for PTSD and GAD in Gulf War

veterans compared with non-deployed personnel were statistically significantly higher than the

summary ORs of PTSD and GAD in Afghanistan/Iraq War veterans respectively. The summary

odds of depression were higher in Gulf War veterans than in Afghanistan/Iraq War veterans and

this narrowly missed statistical significance. Substance use disorders were relatively under

researched, with a small number of studies having been identified through the systematic review.

The meta-analytical ORs of multisymptom illness and of CFS in 1991 Gulf War veterans compared

with non-deployed personnel were elevated. There were no studies identified through the search

strategy for the systematic review of multisymptom illness and of CFS in Afghanistan and Iraq War

veterans.

Table 16 summarises the main meta-analysis summary ORs for psychological disorders,

multisymptom illness and CFS, and the assessment of difference between the summary ORs in

Gulf War veterans and in Afghanistan/Iraq War veterans where applicable.

Table 16 Main meta-analysis summary odds ratios for psychological disorders, multisymptom illness and chronic fatigue syndrome (CFS) in Gulf War, Afghanistan/Iraq War veterans compared with non-deployed personnel

Main health outcome Gulf War veterans

OR (95% CI). I2

Afghanistan/Iraq War veterans

OR (95% CI). I2

P-value for the test for equality of the summary OR

Depression 2.28 (1.88-2.76). I2=75% 1.58 (1.14-2.17). I2=98% 0.055

Dysthymia or chronic dysphoria

2.39 (2.0-2.86). I2=0% n.a. n.a.

PTSD 3.39 (2.79-4.13). I2=53% 2.12 (1.65-2.72). I2=97% 0.004

Alcohol use disorders 1.33 (1.22-1.46). I2=14% 1.36 (1.11-1.66). I2=77% 0.862

Substance use disorders 2.13 (0.96-4.72). I2=29% 1.14 (1.04-1.25). I2=0% 0.053

Any substance use disorder 1.35 (1.25-1.46). I2=0% * n.a.

Generalised anxiety disorder 3.04 (1.95-4.75). I2=35% 1.20 (1.00-1.44). I2=0% Respective 95% CI did not overlap

Multisymptom illness 2.74 (2.15-3.51). I2=92% † n.a.

CFS 7.62 (3.91-14.85). I2 = 52% † n.a.

n.a. Not applicable.* ‘Any substance use’ outcome was measured in Afghanistan/Iraq War veterans’ study (78) and was reported separately.

127

† There were no studies identified of multisymptom illness or CFS in Afghanistan/Iraq War veterans.

The mental health in reservists compared with active duty/regular veteran personnel post

deployment has been of concern in relation to the increased proportion of US or UK National

Guard or reservist forces deployed to Afghanistan/Iraq (111-114), and although the relationship

between active or reservist status on psychological health post deployment was not a primary

research question in this project, regular versus reservist status was a subgroup analysis

undertaken for a limited number of psychological outcomes. There were no important differences

in the likelihood of PTSD in reservists compared with regular personnel deployed to the Gulf War

or to Afghanistan/Iraq War. The summary estimate of the likelihood of alcohol use disorders was

slightly higher, but not statistically significant, in reservists compared with regular personnel

deployed to Afghanistan/Iraq War.

This series of systematic reviews and meta-analyses of international literature had several

strengths. Studies were identified through a search using multiple electronic databases from 1

January 1990 to 24 January 2014. Two study team members independently reviewed abstracts

and assessed possible papers for eligibility. We assessed the overall risk of bias in individual

studies that were included in the systematic reviews and meta-analyses, which was not performed

in other reviews (11, 15, 24, 26) of a similar nature, and the robustness of the results to risk of bias

through subanalysis. However, many of these previous reviews discussed essential biases of

included studies individually, and a narrative description of the studies, but this is not as strong as

a formal assessment of risk of bias.

Our rigorous methodology of only including studies with a military non-deployed comparison group

eliminated many methodological concerns of the previous reviews in the field by concentrating on

the psychological outcome or multisymptom illness or CFS as the condition of interest, and which

may have included papers which used civilian comparison groups. We excluded treatment

seeking self-selected populations that are more likely to experience higher rates of disorders and

may not be representative of the overall military population that were deployed. We also excluded

several well conducted prevalence studies that did not have any military comparison group, since

comparing prevalence studies using different methodologies makes it very difficult to ascertain

whether the differences in associations were due to difference in deployment or different

methodologies used in the studies rather than comparison with similar but non-deployed military

personnel (37). A limitation was the small number of studies identified in some reviews, such as

reported substance use disorders in Gulf War and Afghanistan/Iraq War veterans, which limited the

statistical power in some meta-analyses that involved a small number of studies and also limited

the capacity to undertake further subgroup analyses for some outcomes. However, given our

extensive search methodology, we consider it unlikely that we missed relevant literature.

128

Our systematic reviews and meta-analyses included studies across veteran cohorts from the US,

UK, Australia, Germany and Canada, the majority of which sampled across all three services. The

deployed forces of the countries from which the veteran cohorts were selected varied, but the

included studies all included a non-deployed comparison group and the majority adjusted for

possible demographic and military service confounding factors. The main aim in these systematic

reviews was to consider the summary ORs comparing the health outcome of interest in deployed

compared with non-deployed personnel combining the ORs from the eligible studies.

Although PTSD has often received more attention and publicity in relation to military and veterans’

health, we are not aware of any previous systematic reviews that have estimated comprehensively

the risk of depression, alcohol use disorders, substance use disorders, and GAD in Gulf War and

Afghanistan/Iraq War veterans. Our systematic reviews have extended and updated previous

reviews undertaken for multisymptom illness and chronic fatigue and symptom based conditions

and have also undertaken meta-analyses for the first time.

Multisymptom illness and CFS have been identified contextually more with the 1990-1991 Gulf War

than with deployments to Afghanistan and the Iraq War. However, to the knowledge of the authors

of this report, a comprehensive systematic review of the literature on these symptom based

conditions in veterans of other deployments to this area of operations, has not been undertaken.

The eligibility criteria in our systematic review for inclusion of studies regarding multisymptom

illness and CFS included internationally accepted case definitions for the epidemiological study of

these conditions (19, 20, 27, 35). The US IOM 2014 report on development of a consensus

definition on chronic multisymptom illness (115) was published towards the end of the research

process, but the IOM Committee recommended that the US Veterans Affairs (VA) consider the use

of the CDC definition (and Kansas definition (29)) of multisymptom illness because they capture

the most commonly reported symptoms by Gulf War veterans.

Gulf War veteran health studies used a variety of definitions to investigate fatigue related outcomes

in veterans including chronic fatigue caseness based on the Chalder Fatigue Scale (116), however

we used the more rigorous 1994 international definition (19, 35) for defining CFS as the outcome

measure for inclusion. It is possible that studies of Afghanistan and Iraq veterans have assessed

fatigue in veterans based on less rigorous definitions than CFS, including screening instruments

and scales, but these were not considered in this review. There are also various other approaches

to defining multisymptom illnesses in Gulf War veterans, including defining Gulf War illnesses, that

were not included in our review, based on our eligibility criteria.

The focus of each of the systematic reviews was the outcome under consideration, eg depression

or PTSD or alcohol use disorder. We recognise that many Gulf War veterans and comparison

group subjects with depression, for example, may also meet criteria for other psychological

129

disorders including PTSD, substance use disorders, and anxiety disorders (1, 117). A detailed

examination of this comorbidity between psychological disorders, however, was beyond the scope

of this review and would detract from the primary focus.

Undertaking these systematic reviews has assisted in drawing conclusions about consistency of

the results of studies in relation to psychological outcomes in Gulf War veterans, Afghanistan and

Iraq War veterans, and multisymptom illness and CFS in Gulf War veterans compared to personnel

who were not deployed to a war zone or who were deployed elsewhere. Conducting meta-

analyses and presenting the outputs produced visual and comparable summary effect estimates of

these outcomes in Gulf War veterans, Afghanistan and Iraq War veterans compared with non-

deployed military personnel and quantified this in overall summary measures. By reporting

summary estimates, it is easier and quicker for readers of this report, including health policy

makers and service providers, non-researcher veterans, and clinicians to gain an overview of the

relevant literature.

8 Implications of findingsAn important finding from the current systematic reviews and meta-analyses is that virtually all of

the psychological disorders under study of depression, PTSD, alcohol use disorder and substance

use disorders, and GAD were elevated in troops deployed to the Middle East area of conflicts over

the past 20 years compared with non-deployed military personnel. Although much attention and

general awareness has focused on PTSD and the increased risk of PTSD associated with

deployment to war and conflict zones, substantially less has focused on depression and other

psychological disorders. These systematic reviews and meta-analyses show that these

psychological conditions are also elevated in Gulf War and Afghanistan/Iraq War deployed

compared with non-deployed personnel and poorer psychological health is not restricted to PTSD.

A further important finding is that the odds of multisymptom illness and CFS were significantly

elevated in Gulf War veterans compared with non-deployed military personnel. Studies meeting

the inclusion criteria for the systematic review of multisymptom illness and of CFS were identified

in Gulf War veteran study populations, but not in Afghanistan or Iraq War veteran study

populations. This could suggest that these conditions were not a primary concern or complaint in

the context of Afghanistan/Iraq War veterans’ health. It is somewhat surprising that studies of

Afghanistan/Iraq War veterans did not include a case definition of multisymptom illness or CFS

similar to that employed in studies of previous veterans to that conflict zone, however they may

have employed alternative or less rigorous definitions that did not meet our inclusion criteria.

130

The most likely reason for the finding of increased alcohol use disorders and substance use

disorders is that alcohol and other drugs are being used to “self-medicate” – to ameliorate other

psychological or physical problems (118). This seems a plausible explanation given the high rates

of depression and other psychological conditions in troops deployed to the Gulf War (11) and to the

Afghanistan/Iraq War (73). Although the small numbers of studies of substance use disorders in

Gulf War veterans limited power to detect a statistical difference between the study groups, stigma

around illicit substances may have resulted in some underreporting of other substance abuse. The

military handles alcohol and tobacco, legal substances, very differently to illicit substances.

Based on random-effects meta-analysis in the eligible studies, there was an increased odds of

depression and of PTSD in deployed Afghanistan/Iraq War veterans compared with non-deployed

personnel. However, there was a very high amount of statistical heterogeneity in each of the main

analyses, so the actual size of the increased meta-analytic effect should be interpreted with

caution. No explanation, investigated through subanalyses, was found for this high heterogeneity.

Possible explanations for consideration are that 1990-1991 Gulf War veterans who are now older

have more chronic conditions, which have stabilised, whereas psychological conditions in younger

veterans of more recent conflicts fluctuate more. It is well established that there is a dose

response relationship between combat exposure and PTSD, an underlying factor in the

heterogeneity observed in the meta-analysis of the association between PTSD and

Afghanistan/Iraq War deployment compared with that in the meta-analysis of PTSD and Gulf War

deployment may be a greater variation in the types of experiences veterans had in the more recent

conflicts in the Middle East. Other Afghanistan/Iraq War deployment related factors such as the

possibility of multiple deployments, variables within deployments, the chronicity of the overall

deployment period, and the potential for other deployments at a time of increased operational

tempo may also have contributed to this observed heterogeneity.

The odds of psychological disorders were all slightly greater in Gulf War veterans and the

summary ORs for PTSD and GAD were statistically significantly higher than in Afghanistan/Iraq

War veterans, and may reflect a level of chronicity. Psychological disorders tend to increase post

deployment; the rate of onset of symptomatology of each broad DSM-IV diagnostic category was

found to peak in the first two years following the Gulf War, in Australian Gulf War veterans, and

then subsided. This pattern was particularly noticeable in the case of alcohol disorders (117).

The presentation of idiopathic physical symptoms including multisymptom illness and fatigue

related conditions including symptoms of fatigue and chronic fatigue are likely to be to the person’s

general medical practitioner. The presentation of these symptoms and conditions are not as likely

to be through the mental health system. With overall increased odds of multisymptom illness and

of CFS in Gulf War veterans, departments of veterans’ affairs (Australian and overseas) need to

131

work with general practitioners and primary care providers in relation to this symptomatology and

symptom burden and conditions.

Our findings have important policy and program implications. About 697,000 US troops were

deployed to the 1991 Gulf War, with other coalition forces (from countries such as the UK, France,

Canada and Australia) amounting to nearly 260,000 at their peak personnel strength (119). Over

two million US veterans have deployed to the Afghanistan and Iraq conflicts (120) in a coalition of

49 countries with the UK providing the second largest force. Increased risk of any condition in

veteran populations of these sizes is clearly a concern.

While disorders such as PTSD and depression have been the primary focus, it is also important

that the elevated risk of substance use disorders in veterans is recognised, as there is a strong

association between those disorders and substance use disorders (121, 122). Furthermore,

individuals with PTSD and depression co-occurring with substance use disorders often have worse

treatment outcomes (123). Substance (and alcohol) use disorders are particularly troubling

because of the powerful impact on behaviour, on the individual’s health as well as impacts on

family, community and society as a whole, in addition to the difficulties in diagnosis and

management of comorbid disorders (124).

Further, there are circumstances and exposures associated with the Afghanistan and Iraq War

deployments which may render a systematic review of the literature thus far highly pertinent. For

example, the level of traumatic brain injury from these deployments has been associated with

increased psychiatric illness outcomes (125). An examination of the relationship between

traumatic brain injury and psychological disorders was not in the scope of this review.

An investigation by Hoge (73) reported that combat duty in Iraq was associated with high utilisation

of mental health services and attrition from military service after deployment, and that the high rate

of mental health services utilisation post-deployment is a challenge for resource allocation. In the

context of our reviews which have found the summary OR for the odds of all psychological

disorders to be elevated in Afghanistan/Iraq War veterans and virtually all in Gulf War veterans this

finding has important implications for health service policy and delivery.

9 Implications for future researchOur systematic review showed that substance use disorders were generally under researched. For

example, further studies with increased power are needed to assess substance use disorder risk in

Gulf War veteran populations, and this is a consideration for future research studies.

132

Our systematic reviews considered psychological health outcomes, multisymptom illness and CFS

and considered possible explanations for heterogeneity across studies. The methodology could be

extended to assess the effect of important risk factors for these health outcomes, including military

service exposures, different types of forces deployed e.g. branch of service, and vulnerable

populations e.g. gender differences in deployed personnel. The differences that were observed in

the summary ORs in health outcomes between Gulf War veterans and Afghanistan/Iraq War

veterans could be compared again in the future, repeating the search and systematic review to

update the studies and the meta-analyses, to investigate whether the differences change over

time.

Influences on health outcomes are multifactorial but the influence of cultural factors and veteran

and general population health care systems and services and uptake of those services for the

health outcomes of interest could provide a useful comparison between countries that have

deployed forces to the same conflicts, identify potential gaps, and service as an evidence base for

future interventions.

10 ConclusionOur systematic reviews and meta-analyses found that depression, PTSD, alcohol use disorder and

GAD were elevated in Gulf War veterans and Afghanistan/Iraq War veterans compared with non-

deployed military personnel, with statistically significant higher risks found for Gulf War veterans’

summary odds in relation to PTSD and GAD compared with Afghanistan/Iraq veterans. Any

substance use disorders (i.e. alcohol and/or other substance use disorders) were elevated in Gulf

War veterans compared with non-deployed personnel, and substance use disorders were elevated

in Afghanistan/Iraq War veterans compared with non-deployed military personnel, but further

studies with increased statistical power are needed to assess the association with substance use

disorders in Gulf War veterans. Our systematic reviews and meta-analyses also found that the

odds of multisymptom illness and CFS were significantly elevated in Gulf War veterans compared

with non-deployed military personnel, and no studies of Afghanistan/Iraq War veterans met the

inclusion criteria for review of these disorders.

A further important finding is that the odds of multisymptom illness and CFS were significantly

elevated in Gulf War veterans compared with non-deployed military personnel. Studies meeting

our eligibility criteria were not identified in Afghanistan/Iraq War veterans. Idiopathic symptoms

contributing to multisymptom illness and CFS are more likely to present to general practitioners

than through the mental health system and Veterans’ Affairs departments could work with general

and primary care providers to address this burden of symptom reporting.

133

The main aim of these systematic reviews and meta-analyses was to consider the summary ORs

comparing the health outcome of interest in deployed compared with non-deployed personnel

combining the ORs from the eligible studies. However, the methodology could be extended to

assess the effect of important risk factors for these health outcomes, including different types of

forces deployed e.g. branch of service, military service exposures, and vulnerable populations e.g.

gender differences. This body of research has highlighted some key areas that warrant

consideration for policy makers and future researchers including cultural differences, the length of

time since the war and deployment and the impact on health, the influence of veteran and general

population health care systems between countries that are some of the factors that influence

health outcomes and could be compared as a basis for future policy development and intervention.

134

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